TW201107311A - Compounds for the reduction of β-amyloid production - Google Patents

Abstract

The present disclosure provides a series of compounds of the formula (I) which modulate β -amyloid peptide (β -AP) production and are useful in the treatment of Alzheimer's Disease and other conditions affected by β -amyloid peptide (β -AP) production.

Description

201107311 VI. Description of the Invention: [Technical Field] The present invention relates to the treatment of Alzheimer's Disease (AD) and β-classes using a compound which is an inhibitor of β-type amyloid (Αβ) production. A method of other conditions associated with starch production. The invention further relates to pharmaceutical compositions comprising such compounds. [Prior Art] ^ A Hwang's disease (AD) is a progressive neurodegenerative disease that begins with memory loss and progresses to include severe cognitive impairment, behavioral changes, and decreased motor function (Grundman, Μ. et al. , drc/z TVewro/· (2004) 61. 59-66 'Walsh, DM et al., JVewrow (2004) 44: 181-193). It is the most common form of dementia and represents the third leading cause of death following cardiovascular and cancer. The cost of AD is enormous and includes the suffering of patients and families and the loss of productivity of patients and caregivers. There is currently no treatment to effectively prevent AD or reverse clinical symptoms and potential pathophysiological changes φ. Clearly diagnosing whether a patient with dementia has AD requires histopathological evaluation of the number and location of neuritic plaques and neurofibrillary tangles after necropsy (Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiol Aging (1997) 18 : Sl-2) 类似 Similar changes were observed in patients with chromosome 21 trisomy (Down syndrome). The plaque is mainly composed of β-type starch (Αβ) peptide, while the Αβ peptide is produced by the gradual protein cleavage of the starch-like precursor protein (ΑΡΡ) by β-position cleavage enzyme (BACE), and the γ-secretase step-by-step protein 149653 .doc 201107311 cleavage produces C-terminus (Senc〇e, D), heart y (2〇〇ι) 81. 741-766) «γ-secretase is a transmembrane protein complex that includes the Niccass group (NiCastrin), Apw, ρΕΝ_2 and presenilin-i (psi) or presenilin 2 (PS-2) (Wolfe, MS et al., heart (8) "(2〇〇4) 3〇5: 1119_ 1123). sPS-1 and PS-2 contain the catalytic site of γ-secretase. Αβ4〇 is the most abundant synthetic Αβ form (8〇% 9〇%), and human ^^ is most closely related to the pathogenesis of ad. Mutations in the APP, PS_i and ps_2 genes cause rare familial AD, and it is concluded that Αβ42 aggregates are the main parent material (Selkoe, DJ, household six as / ^ev, (2〇〇!) 81: 741-766 There is currently evidence that recruitment, fibrils, and intracellular Αβ42 play an important role in this disease process (Cleary, Jp et al., (2〇〇5) 8: 79-84). Inhibitors such as gamma-secretase represent therapeutic agents for the potential improvement of AD. There is evidence that the inhibition of gamma-secretase reduces cerebral palsy beta levels and prevents the onset and progression of ad (Selkoe, D. with less 仏/· Hv· (2001) 81: 741-766; Wolfe, Μ” X Med. C/ze. (2001) 44: 2039-2060). Recent data show the role of Αβ in other diseases, including mild cognitive impairment (MCI), Down's syndrome, brain amyloplasty (Caa), dementia with Lewy bodies (DLB), and muscles. Atrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM), and age-related macular degeneration are beneficially used to treat gamma-secretase and compounds that reduce Αβ production for the treatment of these or other Aβ-dependent diseases. Excessive Αβ production and/or reduced clearance can cause CAA (Thal, D. et al. » J. Neuropath. Exp. Neuro. (2002) 61: 282-293) » ^ 149653.doc 201107311 Deposition causes vascular wall degeneration and aneurysms, which may be responsible for 1% to 15% of hemorrhagic stroke in elderly patients. As in AD, mutations in the gene encoding Αβ cause early-onset CAA, called cerebral hemorrhage with amyloidosis of the Dutch type, and mice expressing this mutant protein develop similarly to patients. CAA. Compounds that reduce the Αβ content can reduce or prevent CAA. ^ DLB shows hallucinations, delusions, and parkinsonism. Interestingly, familial AD mutations that cause Αβ deposition can also cause Lewy bodies and DLB symptoms (Yokota, 0_ et al, Jcia (2002) 104: 637-648). In addition, Αβ deposition in sporadic DLB patients is similar to AD (Deramecourt, V. et al., // TV'ewropai/io/ (2006) 65: 278-288). Based on this data, Αβ may promote the pathology of Lewy bodies in DLB, therefore, compounds that reduce Αβ content may reduce or prevent DLB. Approximately 25% of patients with ALS have significant dementia or aphasia (Hamilton, R. L. et al., Acta Neuropathol (Berl) (2Q04) 107 . 515-522). Most (about 60%) of these patients (designated ALS-D) contain ubiquitin-positive inclusion bodies containing predominantly TDP-43 protein (Neumann, M. et al., plus e (2006) 3 14: 130-133). Approximately 30°/〇 ALS-D patients have a class of pink spots associated with dementia-causing β (Hamilton, R. L. et al., 乂cia iVewropai/io/ (2004) 107: 515-522). Such patients should be identified with a starch-like developer and may be treated with a compound that reduces the Aβ content.

IBM is a rare age-related skeletal muscle degenerative disease. The appearance of Αβ sediments in IBM muscles and the reappearance of APP in the muscle of mice by over-expressing APP 149653.doc 201107311 can demonstrate the role of Αβ in IBM (Murphy, Μ·Ρ. Et al., 7Vewro/og_y (2006) 66: Commentary in S65-68). Compounds that reduce the Αβ content can reduce or prevent IBM. In age-related macular degeneration, Αβ is identified as one of several components of choroidal fistula (extracellular deposits under retinal pigment epithelial cells (RPE)) (Anderson, DH et al., Λα (2004) 78: 243- 256). Recent studies have shown a potential link between Aβ and macular degeneration in mice (Yoshida, Τ. et al., C/k / ηναί (2005) 1 15: 2793-2800). Increased Αβ deposition and nuclear cataract have been found in AD patients (Goldstein, L.E. et al., (2003) 361: 1258-1265). Compounds that reduce Αβ levels can reduce or prevent age-related macular degeneration. Compounds that inhibit gamma secretase may also be useful in the treatment of conditions associated with demyelination, such as multiple sclerosis (Watkins, T. et al., Neuron (2008) 60: 555-569). Recent studies by researchers at the Georgetown University Medical Center have shown that γ-secretase inhibitors can prevent long-term damage from traumatic brain injury (Loane, DJ et al., TVaiwre Me Hawthorn Beta (2009): 1- 3). A reasonable way to reduce the Αβ content is to block the action of secreted enzymes. An adjunct method is to selectively reduce Αβ1-42 production under the action of certain compounds that direct γ-secretase-mediated sputum cleavage and instead generate a shorter form of Αβ. These shorter forms appear to be less susceptible to aggregation, and the shorter form of Αβ has a lower solution neurotoxicity than Αβί·42 (see Barten, Donna Μ.; Meredith, Jere E., Jr.; Zaczek, Robert; Houston, John G.; 149653.doc 201107311

Albright, Charles F. Drwp ζ·« ΛάΖ) (2006), 7(2), 87-97). Therefore, 'selectively reducing the compound produced by Aβ1-42 and its pharmaceutical composition is a beneficial agent' which will prevent the damage caused by excessive production of Aβ, and is suitable for the treatment of Alzheimer's disease, Down syndrome, CAA and Inclusion body myositis, DLB and other conditions that produce excessive Αβ. SUMMARY OF THE INVENTION In a first aspect of the invention, the invention provides a compound of formula (1), hydrazine, hydrazine, D, hydrazine (1) or a pharmaceutically acceptable salt thereof, wherein hydrazine contains from 1 to 3 independently a 5- or 6-membered heteroaryl ring selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the heteroaryl ring is optionally selected from 1 or 2 selected from the group consisting of a dentate group, a halogen C.·6 alkyl group, a hydroxyl group, an amine group, and a Cm alkane. The groups of the oxy group and the alkyl group are substituted; the B group is far from the group. ratio. Wherein the phenyl and n are substituted with one or two substituents independently selected from the group consisting of: (^^ alkoxy, C, -6 alkyl, Cw alkylamino-Ci) 6 alkoxy, cyano, Cl_3 dialkylamino-Cu alkoxy, halo, halo C!·6 alkoxy, halo Cw alkyl, hydroxy, decylamino and amine; D is selected from

149653.doc 201107311

From hydrogen, c]_4 alkoxy" "^ indicates the point of attachment to the nitrogen atom of the parent molecule" means the point of attachment to the "E" moiety; b is selected from hydrogen, C丨.6 alkyl. 2-6 alkenyl and hydroxy...is VII, wherein RX&Ry is independently selected from the group consisting of Ci-4 alkoxy CN4 alkyl, Cl_4 alkoxycarbonyl, Ci6 alkyl, cycloalkyl, (CM cycloalkyl) The alkyl moiety of the C1-4 alkyl group, the hydroxyalkyl group and the trimethyl group, the octa (C3·7^alkyl)Ci_4 alkyl group may be optionally substituted by a* alkoxy group; or Rx together with the nitrogen atom to which it is attached Forming a 4- to 7-membered monocyclic or bicyclic ring containing, as appropriate, a double bond and optionally a heteroatom selected from the group consisting of hydrazine, NRZ &s; wherein the RZ is selected from the group consisting of hydrogen, Ci6 alkyl, and Ci4 alkoxy group; And wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of Cw alkoxy, Ci. 6 alkyl 'functional, halogen c, _4 alkyl, hydroxy, -NRfRg, pendant oxy (螺x〇), spiro dioxolanyl; which allows Rf and Rg to be independently selected from hydrogen, Cm alkoxycarbonyl, and (: "alkyl;

Re is selected from the group consisting of hydrogen, Ci. 4 alkylsulfonyl, Ci_4 alkylsulfonylamino, amine, Ci. 6 alkylamino, C|6 dialkylamino, c3·? Amino group, via I49653.doc 201107311 base and cN4 alkoxy group;

Rd is selected from the group consisting of hydrogen, CN6 alkyl, Cw alkoxy Cw alkylcarbonyl, Cm alkoxycarbonyl, Cw alkylcarbonyl, Cw alkylsulfonyl, C3.7 cycloalkylsulfonyl, C3·7 ring Alkylcarbonyl, Cw dialkylamino Cw alkylcarbonyl and halogen C!·4 alkyl' wherein the alkyl moiety of alkoxycarbonyl, alkylcarbonyl and alkylsulfonyl is optionally selected from Cw Substituted with a substituent of an alkylamino group and a Cw alkoxy group; and φ E is selected from the group consisting of C, -6 alkyl, C 4-6 cycloalkyl, (C 4 7 cycloalkyl) Cm alkyl, phenyl fluorenyl, phenyl and 1 or 2 nitrogen atoms to 5 to a heteroaryl ring, wherein the phenyl group, the phenyl group of the benzyl group and the heteroaryl ring are each independently selected from Cm alkyl, Cl-6 alkyl by 1, 2 or 3 Substituents for the oxy group, the cyano group, the dentate group, the hydroxyl group of the Ci 6 and the substituent of the iS C!·6 alkyl group. The present invention is directed to such compounds as well as other important objects as described below. [Embodiment] In a first embodiment of the first aspect, the present invention provides a compound of the formula (I) as defined above, or a pharmaceutically acceptable salt thereof, wherein A is one to three nitrogen atoms. a 5-membered heteroaryl ring; and wherein the heteroaryl ring is optionally substituted with a group selected from a halogen group and a Cw alkyl group. In the second embodiment, the B series is selected from the group consisting of phenyl groups and. Than the sulfhydryl group, which is phenyl and hydrazine. The base is optionally substituted with 2 or 2 substituents independently selected from C -6 alkoxy and halo. In the third embodiment, the case is replaced by 1, 2 or 3 independently selected from the group consisting of Ci 6 yard base, cardiooxy group, aryl group, dentate group, _Cl·6 alkoxy group and dentate k group. Substituted phenyl. In the fourth embodiment, the 0 is selected from 149653.doc 201107311

In the fifth embodiment, '1^> is _NRXRy ' wherein RX& Ry is independently selected from the group consisting of hydrogen, cN4 alkoxy Cw alkyl, cU6 alkyl, c3 7 cycloalkyl 'hydroxy c'. And a trimethylidene group in which the alkyl moiety of the (CM cycloalkyl)Ci4 alkyl group may be optionally substituted with a Cw alkoxy group. In a sixth embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; wherein the heteroaryl Cycling is replaced by a group selected from the group consisting of a dentate group and a C 6 alkyl group; B is selected from the group consisting of a phenyl group and a π ratio. The phenyl group and the π group are preferably independently selected from the group consisting of Cl. • 6 alkoxy and a substituent of a dentate group; E is optionally oxime, 2 or 3 independently selected from Cw alkyl, Cw alkoxy 'cyano, li, iCl 6 ; oxy and ^ a substituent substituted with a phenyl group; D is selected from

: and ; and

Rb is -NW, wherein RjRy and the nitrogen atom to which it is attached - (iv) optionally contain 4 to 7 members of a monocyclic or bicyclic ring selected from 0 and other heteroatoms; wherein RZ is selected from the group and Ci. Wei, and wherein the Jf is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C, 6 Oxygen 149653.doc 201107311, c]-6 alkyl, halo, haloCl 4 alkyl , hydroxy, _NRfRg, pendant oxy and spiro dioxolanyl; wherein Rf and Rg are independently selected from the group consisting of hydrogen, Cm alkoxycarbonyl and Cw alkyl. In a seventh embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: VIII is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; The aromatic ring is optionally substituted with one group selected from a group and a C group; the lanthanide is selected from the group consisting of phenyl and . Pyridyl, wherein the phenyl and acridine groups are optionally substituted by j or 2 substituents independently selected from the Cl-6 alkoxy group and the yl group; , 2 or 3 phenyl groups independently selected from the group consisting of Ci decyl, Ci 6 alkoxy cyano, dentyl, _ C! 6 alkoxy and -6 alkyl; and D system from

Rb

In an eighth embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; wherein the heteroaryl The ring view is substituted with one group selected from the group consisting of a base group and a Cw alkyl group; and the B group is selected from the group consisting of a phenyl group and a phenyl group, wherein a phenyl group is used. The time base is optionally substituted with a substituent independently selected from the group consisting of C!·6 alkoxy groups and a halogen group; E is optionally selected from Cm alkyl, k oxonite cyanide by 1, 2 or 3 Substituents for the base group, |S c丨·6 alkoxy group and !I c丨_6 alkyl group are substituted for the phenyl group of 149653.doc 201107311;

Rb is -NRxRy, wherein Rx and Ry are independently selected from the group consisting of hydrogen, Cl**alkoxy C!·4 alkyl, Cw alkyl, Ο:3·; cycloalkyl, hydroxy€4 alkyl and three A mercapto group in which the alkyl portion of the (C3_7 cycloalkyl)Cu4 alkyl group may be optionally substituted with a c14 alkoxy group. In a ninth embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; wherein the heteroaryl Cyclic conditions are substituted by a group selected from a halogen group and a c-alkyl group; B is selected from a phenyl group and a pyridyl group, wherein the phenyl group and the acridinyl group are independently selected from Cl or 1 or 2; 6 alkoxy and a substituent of a dentate group; E is optionally selected from 1, 6 or 3 independently from Ci 6 alkyl, Ci 6 alkoxy, cyano, halo, halogen C 6 · alkane a phenyl group substituted with a substituent of an oxy group and a haloalkyl group;

, R is -NW, wherein ^ and ... together with the nitrogen atom to which they are attached form a 4- to 7-membered monocyclic ring or an I49653.doc 12 201107311 bicyclic ring optionally containing another hetero atom selected from fluorene and NRZ; wherein Rz is selected from a Cw alkyl group and a Cm alkoxycarbonyl group; and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of Ci 6 alkoxy, C!-6 alkyl, halo, halogen Ci*alkyl, Hydroxy, _NRfRg, pendant oxy and spiro dioxolanyl; wherein Rf&Rs are independently selected from the group consisting of hydrogen, Ci4^ oxycarbonyl and Cm alkyl. In a tenth embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; wherein the heteroaryl Cyclic conditions are substituted by a group selected from a group and a C 6 alkyl group; B is selected from a phenyl group and a pyridyl group, wherein the phenyl group and the n-pyridyl group are independently selected from the group consisting of Cl_6 alkane by 1 or 2 Substituted by a substituent of an oxy group and a functional group; E is optionally selected from the group consisting of Ci 0 alkyl, Ci-alkoxy, cyano, dentate, _Cl 6 alkoxy, and _Cl· by i, 2 or 3 a phenyl group substituted with a 6 alkyl group; and D is selected from

In an eleventh embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring having 1 to 3 nitrogen atoms; The aromatic ring is optionally substituted with one group selected from the group consisting of _ group and C _6 alkyl group; the B group is selected from the group consisting of a phenyl group and a pyridine group, wherein the phenyl group and the acridine group are independently selected by one or two. Substituted from a substituent of Ci.6 alkoxy group and _ group; 149653.doc 201107311 E is optionally selected from C,·6 alkyl, c]·6 alkoxy, cyanide by 1, 2 or 3 independently. a phenyl group substituted with a substituent of a base, a yl group, a Ci_6 alkoxy group and a halogen C. 6 alkyl group;

Rb is -NRxRy, wherein Rx and Ry are independently selected from the group consisting of hydrogen, Cl.4 alkoxy Cl. 4 alkyl, C.6 alkyl, C3.7 cycloalkyl, and trans-C!.4 alkyl. And a trimethylmethyl group in which the alkyl portion of the (C3_7 cycloalkyl)CN4 alkyl group may be optionally substituted by a ci4 alkoxy group. In a twelfth embodiment of the first aspect, the present invention provides a compound of the formula (1) Or a pharmaceutically acceptable salt thereof, wherein: A is a 5-membered heteroaryl ring containing 1 to 3 nitrogen atoms; wherein the heteroaryl ring is optionally subjected to a base ring selected from the group consisting of a _ group and a C1-6 alkyl group. Substituted; lanthanide is selected from the group consisting of phenyl and pyridyl, wherein the strepyl and pyridyl groups are optionally treated by work or two substituents independently selected from the group consisting of Cl. 6 alkoxy groups and groups; And 2 or 3 phenyl groups independently selected from the group consisting of Ci 6 alkyl, C|-6 alkoxy, cyano, halo, Cw alkoxy and substituents from an alkyl group; D is selected from

149653.doc 201107311

Rb is -NRxRy 'wherein Rx and V together with the nitrogen atom to which they are attached form a 4- to 7-membered monocyclic indole bicyclic ring optionally selected from the group consisting of hydrazine and other heteroatoms of NRzi; wherein Rz is selected from Cw alkyl and Cl.4 Alkoxycarbonyl; and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of Ci 6 -oxy, C!-6 alkyl, halo, halogen Ci. 4 alkyl, hydroxy, _NRfRg, a pendant oxy group and a spiro dioxolanyl group; wherein the Rg system is independently selected from the group consisting of hydrogen, c" a hospital oxycarbonyl group, and (^.6 alkyl group. In the thirteenth embodiment of the first aspect, A The definition is extended to also include sulfhydryl, acetyl, nitrile, CF3, and indifference CH2CN; and the heteroaryl ring may be additionally substituted by CHCF2 and/or CN. In the fourteenth embodiment of the first aspect, B may also In the fifteenth embodiment of the first aspect, as a part of D, ... may also include 802. 丨6 alkyl, ethyl hydrazino and optionally substituted by c "alkyl"

_ where Rh, Ri = H, OH ' or - form c = 〇, C = N_〇H or c = n 〇 c "burning base. In the second aspect, the present invention provides a therapeutic material low A condition in which a powdery form reacts (4) a pharmaceutical composition comprising a substance or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier or diluent. In the needle form, the present invention provides a For therapeutic purposes, the milk animal reduces the condition of the bufa peptide formation reaction comprising administering to the 149653.doc -15- 201107311 mammal a therapeutically effective amount of a compound of formula (i) or a pharmaceutically acceptable compound thereof In a first embodiment of the first aspect, the condition is selected from the group consisting of Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment (MCI), and brain amyloplasty (CAA). , Lewy body dementia (DLB), amyotrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM), age-related macular degeneration, and cancer. In the second embodiment of the third aspect, the condition is It is selected from Alzheimer's disease and Down's syndrome. In a third embodiment of the third aspect, the condition is Alzheimer's disease. Other aspects of the invention may include suitable combinations of the embodiments disclosed herein. Other aspects and examples can be found in the description provided herein. The description of the invention herein should be construed in accordance with the laws and principles of chemical bonding. In some cases it may be necessary to remove the hydrogen atom to accommodate the substituent at any given position. It should be understood that 'the compounds encompassed by the present invention are compounds suitable for stable use as a pharmaceutical agent. Any substituent at a specific position in the molecule or The definitions of variables are intended to be independent of their definitions at other positions in the molecule. All patents, patents, and references cited in this specification are hereby incorporated by reference in their entirety. In the following, the invention (including definitions) will prevail. In some cases, the number of carbon atoms in any of the groups is represented before the group is described. For example, t 'the term "tooth. 16 alkoxy" "Base" means a (tetra)oxy group having 1 to 6 carbon atoms, and the term alkoxy Ci_2 Hyun I49653.doc -16·201107311 base...haves an alkoxy group of 4 carbon atoms Attached to the parent molecular moiety via an alkyl group having one carbon atom. In the presence of such names, it may be substituted for all other definitions contained herein. The singular forms "a" and "the" As used herein, (4) "alkoxy" means that the alkyl group is attached to the parent molecular moiety via an oxygen atom.

The term "alkoxyalkyl" as used herein refers to an alkyl group substituted with 12 or 3 alkoxy groups. As used herein, the term "Xie Oxygen" is attached to the parent molecular moiety via a group. The term "burning oxygen" as used herein means that the alkoxy group is attached to the parent molecular moiety via a plurality of groups. The term "alkyl" as used herein means a radical derived from a straight or branched chain saturated hydrocarbon containing from hydrazine to (7) carbon atoms. The term "alkylamino" as used herein refers to _NHRX, wherein Rx, as used herein, the term "alkylamino alkoxy" refers to an alkyl group attached to the parent molecular moiety through an alkoxy group. The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to the parent molecular moiety via a sulfonyl group. The term "alkylsulfonylamino" as used herein refers to ·c(〇)nhs(〇)2rX, 149653.doc -17- 201107311 wherein Rx is an alkyl group. The term "amine group" as used herein refers to _Nh2. The term "carbonyl" as used herein refers to. The term "cyano" as used herein refers to _CN. The term "cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon ring system having from 3 to 14 carbon atoms and 0 heteroatoms. The term "(cycloalkyl)alkyl" as used herein refers to an alkyl group substituted with i, 2 or 3 cycloalkyl groups. The term "cycloalkylamino" as used herein means _nhrX, wherein R is a cycloalkyl group. The term "cycloalkylcarbonyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group. The term "cycloalkylsulfonyl" as used herein refers to a cycloalkyl group attached to the parent molecular moiety via a scutane. The term "dialkylamino group" as used herein means, wherein Rx & Ry are each an alkyl group. The term "dialkylaminoalkoxy" as used herein refers to a dialkylamino group attached to the parent molecular moiety through an alkoxy group. The term "dialkylaminoalkyl" as used herein means a 1, 2 or 3 dialkylamino group substituted by burning. The term "dialkylaminoalkylcarbonyl," as used herein, refers to a dimeric aminoalkyl group attached to the parent molecular moiety through a carbonyl group. The terms "halo" and "-" as used herein mean f, ^, Br and I. 149653.doc 18-201107311 "haloalkoxy" means an alkyl group via oxo oxime. 1 , 2, 3 or 4 As used herein, the term "hydroxy" means _〇η. The term "trans-study" as used herein refers to a radical substituted with a hydrazine hydroxy group.

The term "methylamino" as used herein refers to _nhch3. The term "sideoxy" as used herein refers to =〇. The term "sulfonyl" as used herein refers to -s〇2_. It is to be understood that the present invention encompasses a physicochemical form or a mixture thereof which is capable of reducing the production of a powder. Certain compounds of the invention may also exist in different conformational forms that can be separated from the knife. Due to, for example, steric or ring stress

The term as used herein is attached to the parent molecular moiety. The term halogen atom is used as used herein. Twisted asymmetry of 2 or 3 and limited rotation about an asymmetric single bond allows for the separation of different conformers. The present invention encompasses each of the conformational isomers of the <cage" The invention is intended to include all isotopes of the atoms occurring in the compounds of the invention. Isotopes include atoms with the same atomic number but different mass numbers. As a general example and without limitation, the hydrogen isotope includes sinking gas. Carbon isotopes, including UC and 14C 'isotope-labeled compounds of the invention, can generally be replaced with other isotopically-labeled reagents by conventional techniques known to those skilled in the art or by methods analogous to those described herein. Prepared without labeling reagents. These compounds have a variety of potential uses, such as 149653.doc 201107311 in stable isotope conditions, pharmacology or pharmacokinetics as a standard and reagent for determining biological activity. These compounds have the potential to promote improved biological properties. Certain compounds of the invention may exist in zwitterionic form in the per- zwitterionic form of such compounds and mixtures thereof. The compounds of the invention may exist in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein denotes a salt or zwitterionic form of a compound of the invention which is water soluble or oil soluble or water dispersible or oil dispersible 'in reliable medical judgment. Within the scope, it is suitable for use in contact with patient tissues, and it is beneficial to achieve superior benefit/risk ratio and is effective in achieving efficiencies, stimuli, irritation, allergic reactions or other problems or complications. Its intended use. Such salts can be made during or after the final isolation and purification of the compound. The nitrogen atom is reacted with a suitable acid to prepare separately. Representative acid addition salts include acetates, adipates, alginates, citrates, aspartates, benzoates, benzoates, sulfates, butyrates, camphorates , camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, P-breast _ ^ muscle hexanoate, formate, fumarate, citrate, hydrogen Molybdate, hydrocyanate, 2, thioglycolate, milk: salt, cis-succinic acid salt, mesitylene dihydrochloride, formazan acid salt, naphthalene sulfonate, nicotine Acid salt, 2-naphthalene sulfonate, acid salt, pentanic acid brain (Palm〇ate), pectate, peroxosulfate, 3-phenylpropionate, picrate, pivalic acid Salt, propionate, sulphonate, tartrate, tri-gas acetate, tri-sodium acetate, phosphate, sulphate, carbonate, p-benzoate and decanoate. Examples of acids which can be used to form pharmaceutically acceptable 149653.doc • 20· 201107311 addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid and maleic acid. , succinic acid and citric acid. The base addition salt can be used during the final isolation and purification of the compound by reacting a carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation, or an amine or an organic primary amine, a secondary amine or a tertiary amine. The reaction is prepared. The cations of the pharmaceutically acceptable salts of the sauce include Zhong, Na, Shu, Xi, Zhen and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, monomethylamine, dimethylamine. , triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-mercaptomorpholine, monohexylamine, procaine (pr〇caine), benzhydrylamine, anthracene, anthracene diphenylmercaptophenethylamine and anthracene, Ν'-diphenylmethylethylenediamine.胄 used to form a base-addition salt. He represents an organic amine including ethylenediamine, ethanolamine, diethanolamine, bismuth and travel. When a therapeutically effective amount of a compound of formula (1) and a pharmaceutically acceptable salt thereof The active ingredient may be presented in the form of a pharmaceutical composition when the chemical source is administered to the therapy. Accordingly, the present invention further provides a therapeutically effective amount of a pharmaceutically acceptable salt of the formula (1) or a pharmaceutically acceptable salt thereof and one or more pharmaceuticals. A pharmaceutical composition of a pharmaceutically acceptable carrier, diluent or excipient. The compound of formula (I) and pharmaceutically acceptable salts thereof are as described above. Carriers, diluents or tablets are required. It is acceptable in the sense of being compatible with the other ingredients of the preparation and harmless to the recipient thereof. According to another aspect of the invention, there is also provided a method for preparing a pharmaceutical composition, which comprises a compound of the formula (1) Or a pharmaceutically acceptable salt thereof, in admixture with one or more pharmaceutically acceptable carriers, diluted 149653.doc • 21-201107311. The dosage of the compound of formula I to achieve a therapeutic effect is not limited to, for example, the age of the patient, Weight and sex It depends on the mode of administration and the nature of the drug, and it depends on the degree of β_AP reduction required and the efficacy of the specific compound used in & a曰, <jin. The specific disease condition. Also intended for specific compound I / therapy And the dose can be administered in a unit dosage form' and the early dosage form can be adjusted by the technicians of 孰4 τ5 ^ ·, ', h to reflect the relative activity level. The agent to be used will be the tincture S (and daily The decision of the number of doses is determined by the physician and can be varied to determine the titration dose for a particular situation of the invention to produce the desired therapeutic effect. When parenterally administered, 'for a sputum or may suffer from blood as described herein. · A suitable dose of a mammal (including a human), a phantom compound or a pharmaceutical composition thereof, which produces any related condition, is generally from about 5 mg/kg to about 1 mg/kg per amp, preferably Α n, s. SS flat phlegm about 0.1 to 2 mg / kg. For oral administration, the dose can be about 〇 per kilogram of body weight to about 75 (four), preferably per kilogram of body weight (M to Π ) within the range of mg. The active ingredient is preferably administered in the same dose per day! Up to 4 times. However, small doses are usually administered and the dose is gradually increased' until the optimal dose for the subject being treated is determined. The compounds of the invention are preferably administered in a concentration effective to produce a starch-like action without causing any deleterious or undesirable side effects, in accordance with good clinical practice. However, it should be understood that the amount of the compound actually administered should be determined by the physician based on the circumstances, including the condition to be treated, the choice of compound to be administered, the route of administration selected, the age, weight and response of the individual patient, and the symptoms of the patient. The severity is determined. The pharmaceutical formulation may be adapted for administration by any suitable route, for example by oral (including buccal or sublingual), transrectal, nasal, topical (including buccal, 149653.doc -22-201107311 or Percutaneous, vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intracranial, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or intradermal injection or infusion) routes of administration. Such formulations may be prepared by any method known in the art of pharmacy, for example by combining the active ingredient with a carrier or excipient. Pharmaceutical formulations suitable for oral administration can be presented in individual units, such as capsules or lozenges: powders or granules; dissolved in aqueous or non-aqueous liquids

Liquid or suspension; edible foam or foam (whips); or oil-in-water emulsion or water-in-oil emulsion. For example, by oral administration in the form of a key or capsule, the active drug component can be combined with a π-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. The powder is prepared by comminuting the compound to a suitable size: finely divided and mixed with a likewise comminuted pharmaceutical carrier such as an edible carbohydrate dihydrate such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present. The j capsule is made of the (4) final mixture and the filled shaped gelatin outer shell as described above. A slip agent and a lubricant such as colloidal silica, talc, stearic acid, stearic acid or solid polyethylene glycol may be added to the powder mixture prior to the filling operation. A disintegrant or solubilizing agent such as loam, carbonic acid (tetra) or sodium carbonate may also be added to improve the availability of the drug when the capsule is taken. It may also be suitable for adhesives, lubricants, disintegrants and colorants in a mixture of people if necessary or necessary. Suitable binders include starch 'gelatin, natural sugar (such as glucose or β-lactose), corn sweetener, celestial and synthetic rubber (such as acacia, yellow f-gel or sodium alginate), slow methyl fiber 149653.doc • 23- 201107311, polyethylene glycol and its analogues. Lubricants used in such dosage forms include sodium oleate, sodium hydride, and the like. Disintegrators include, but are not limited to, starch, decyl cellulose, agar, bentonite, triterpene, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into a tablet. By mixing a suitably comminuted compound with a diluent or matrix as described above and optionally with a binder (such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrazole), a dissolution delaying agent (such as stone)粉末), a resorption accelerator (such as a quaternary salt) and/or an absorbent (such as bentonite, kaolin or dibasic calcium phosphate) are mixed to prepare a powder mixture. The powder mixture can be granulated by wetting with a binder such as a syrup, starch paste, acadia mucilage, or a solution of cellulose or polymeric material and forcing it through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press and the result is an incompletely shaped mass that breaks into granules. The particles may be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent the particles from sticking to the tablet forming mold. The lubricated mixture is then compressed into a tablet. The compounds of the invention may also be combined with a free-flowing hydrazine carrier and directly compressed into a spinning agent without undergoing a granulation or sizing step. A clear or opaque protective coating consisting of a shellac seal coat, a sugar or polymeric coating, and a polishing coating of tantalum can be provided. Dyestuffs can be added to the coatings to distinguish between different unit doses. Oral liquids such as solutions, syrups and elixirs may be prepared in unit dosage form such that the compound contains a predetermined amount of compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared via the use of a non-toxic vehicle. Solubilizers and emulsifiers may also be added (such as ethoxylated 149653.doc 201107311 isostearyl alcohol and polyoxyethylene sorbate (such as peppermint oil or natural sweeteners, and their analogues, alcohol ethers), preservation Agent, flavoring or saccharin or other artificial sweetness j) Where appropriate, the unit dose formulation administered orally can be microencapsulated. Formulations may also be prepared for prolonged or sustained release, for example by coating or embedding particulate material with a polymer, wax or the like.

The pharmaceutically acceptable salts of the formula (I) &# and its oxime may also be administered in the form of a liposome delivery system such as a single layer of small vesicles, a single layer of large vesicles and a plurality of vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phospholipids. The compound of formula (I) and its pharmaceutically acceptable salts can also be delivered by using a single antibody as the individual carrier to which the compound molecule is coupled. The compounds can also be coupled to a soluble polymer as a targetable drug carrier. The poly deltas may comprise a polyethylene beta ketone ketone, a perylene copolymer, a polyhydroxypropyl methacryl decyl phenol, a polyhydroxyethyl aspartame or a palm sulfhydryl residue. Oxidized ethylene polyisamic acid. In addition, the compounds can be coupled to a class of biodegradable polymers suitable for drug controlled release, such as polylactic acid, poly-ε caprolactone, polybutyric acid, polyorthoesters, poly Acetal, polydihydropyran, polycyanoacrylate and crosslinked or amphoteric hydrogel oxime copolymer. Pharmaceutical formulations suitable for transdermal administration may be presented in the form of individual patches that are intended to remain in intimate contact with the recipient's skin for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986). 149653.doc -25· 201107311 Pharmaceutical formulations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatment of the eye or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient can be used with a stone or water miscible ointment base. Alternatively, the active ingredient may be formulated into a cream together with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations suitable for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations suitable for topical administration to the oral cavity include buccal, tablets and mouthwashes. Pharmaceutical formulations suitable for rectal administration may be presented as a suppository or as an enema. Pharmaceutical formulations suitable for nasal administration and in which the carrier is a solid include a course powder which is administered by nasal inhalation, i.e., by a nasal container filled with a powdered container of the nasal cavity. Formulations suitable for administration as a nasal spray or nasal drops and which are liquid are included as an aqueous or oily solution of the active ingredient. Pharmaceutical formulations suitable for inhalation administration include fine powders or mists which can be produced by means of various types of metered doses of pressurized aerosols, nebulizers or insufflators. Pharmaceutical formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. 149653.doc -26- 201107311 Pharmaceutical formulations suitable for parenteral administration include aqueous and non-oxidative agents which may contain antioxidants, buffering bacteriostatic agents, and solubilities of the formulation and the blood of the intended recipient. Aqueous sterile injectable solutions; and aqueous and nonaqueous sterile suspensions which may include suspending and thickening agents. Formulations may be presented in unit doses or in multiple doses of containers (eg, sealed ampoules and vials) and may be stored under lyophilized (Donggan) conditions, requiring only the addition of a sterile liquid carrier (eg, water for injection) just prior to use. . Injectable solutions and suspensions prepared by the prior art can be prepared from Φ sterile powders, granules and lozenges. It will be appreciated that in addition to the ingredients specifically mentioned above, the formulations may also include other agents which are known in the art to take into account the type of formulation in question, e.g., formulations suitable for oral administration may include flavoring agents. The invention will now be described in connection with certain embodiments that are not intended to limit the scope of the invention. On the contrary, the invention is to cover all alternatives, modifications and equivalents The following examples (including specific examples) are intended to illustrate one embodiment of the invention, which is intended to be used for the purpose of illustrating certain embodiments and the examples are presented to provide a The most useful and easiest to understand description. The compounds of the present application can be synthesized by the methods described below, in conjunction with synthetic methods known in the art of synthetic organic chemistry or by methods known to those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All documents cited herein are hereby incorporated by reference in their entirety. Compounds can be prepared using the reactions and techniques described in this section. The reaction is at 149653.doc -27- 201107311. Suitable solvents for the reagents and substances used. For example, it is suitable for the conversion achieved. In addition, in the following description of the synthesis, all the proposed Reaction conditions (including solvent, anti-B reaction cone, reaction temperature, duration of experiment and selection of treatment procedures), 抒 抒, ^ 评) 7 selected as the standard conditions of the reaction, 孰s this technology should be easy to know These bars... ^ 1 dry cooked 1 organic synthesis technology should be 'the functional groups present on the file must be consistent with the proposed reagents and the substituents compatible with the reaction conditions for those skilled in the art It is readily known that alternative methods must be used. Suitable for the synthesis of the compounds of the invention <% of the starting materials are known to those skilled in the art and can be readily manufactured or commercially available. The following methods are described below for illustrative purposes. It is intended to provide, and is not intended to limit, the scope of the patent application. It should be recognized that it may be necessary to prepare a conventional protecting group to protect the functional (7) B month "based compound' and subsequently remove the protecting group to pay The compounds of the present invention are known to those skilled in the art for the use of protecting groups in accordance with the present invention. Month's, used in this specification (including, in particular, the following exemplary processes and examples), are written by those skilled in the art. Well-known. The abbreviations used are as follows: , , , and the chemical abbreviations used in this specification and examples are defined as follows: "卟一亚节基丙蒙1; "ί-Bu | is flute - Ding ugly. "〇广" is the first Dibutyl 'DCM' is dioxane; LDA is diisopropylamino; "ph" is phenyl; "tfa" is diacetic acid; "~ is ethyl; "_" is the second The base amine II "〇 &" is acetic acid vinegar; "h" is hour, "discussion" is minute; and "THF" is tetrahydrofuran. 149653.doc -28- 201107311 illustrating the method suitable for the production of the compounds of the invention

example. Grab 7-3 outlines the different routes of synthesis of substituted aniline fragments for the preparation of the title compounds. As indicated in the rhythm, a variety of substituted heterocycles 1 (including but not limited to) oxazole, 4·methyl..._carbazole, 4-gas-1//-imidazole under test conditions , 4_(difluoromethyl)anthracene-imidazole) may be added to the substituted gas nitroarene or fluoronitroarene 2, including but not limited to 2_chloro-4_nitrobenzoquinone, to obtain heteroaryl Substituted nitroaromatics 3. The compound 3 is reduced by using a reagent comprising an acidic medium containing iron or by catalytic hydrogenation using a catalyst such as palladium on carbon or other catalyst known to those skilled in the art to obtain a substituted aniline 4. Although mourning? Description of the preparation of 4_(indanidazole-1-yl)aniline 4, but those skilled in the art will recognize that this method is broadly applicable to the synthesis of other 4-heteroarylanilines, including but not limited to 4 - (lf 1,2,4-tris-l-yl)aniline and 4_(1//12,3 triazole-bu)aniline. Alternatively, a substituted nitropyridine may be used in place of the nitroaromatic hydrocarbon of formula 2 to give an amine substituted via. Process 1 Acid or Pd/C'H: R1

A ♦ β 1 2 x=f or α Other procedures for the production of substituted anilines rely on palladium-catalyzed coupling of aryl halides or heteroaryl dentates with _acids (Suzuki coupung reacti〇) n)). As shown in Figure 2, the biaryl anilines 10 and 11 and their nitro precursors 8 and 9 can be substituted by an aryl or heteroaryl phthalate 5 and 7 and a substituted aryl dentate 6 respectively (including i _ bromo 2 • methoxy · 4 nitrobenzene) is coupled to produce. Alternatively, as shown in 衮j, the coupling partner can be inverted 149653.doc -29· 201107311, wherein the aryl halide 丨2 or the heteroaryl halide 丨4 is coupled with the nitroaromatic 1-3 oleic acid vinegar. Substituting the substituted nitroaromatics 8 and 9, respectively. Process 2

These general reaction schemes are intended to illustrate general reaction methods that are highly resistant to a wide variety of functional groups, and such methods are not limited by the particular structure shown in Figures 2 and 3. It is also recognized by those skilled in the art that a similar process, including aryl or heteroaryl complexes with Sterling coupling of aryl or heteroarylstannane, is also used to prepare the desired aniline or its nitrate. An excellent method for the base precursor. The following scheme outlines the different routes of synthesis of 2,4 dichloro-7•aryl-6,7-monohydro-5 open-cyclopenta[d] mouth bites for the title compound. 149653.doc 201107311 As illustrated in 4, cyclopentanone.15 can react with a variety of dentated aryl magnesium to produce a tertiary alcohol 16. These secondary alcohols can be dehydrated in the presence of a dehydrating agent such as a mineral acid or sulfinium chloride to give olefin 17. After treatment with an oxidizing agent such as peroxyacid, the olefin 17 can be converted to 2-arylcyclopentanone 18. Ah Thaher, B.; Koch, P.; Del Amo, V.; Knochel, P.; Laufer, S. 2008, 225-228. Process 4 15 16 17 18 Alternatively, as shown in Figure 5, epoxycyclopentane 19 can be treated with various halogenated aryl magnesiums in the presence of a copper salt such as copper iodide, The resulting alcohol was then oxidized to prepare 2-arylcyclopentanone 18. This oxidation can be carried out by a number of oxidizing agents known to those skilled in the art, using Dess-Martin periodinane to achieve good results.

Dess, D. B.; Martin, J.C. J. 〇rg. Chem. 1983, 48, 4155-4156. Process 5

Other ketones suitable for use in the preparation of the compounds of Scheme 1 can be prepared by the methods described in O. Dirat et al., 2, 6, 彳 7, 1295. This method is described in 遂衮6, which relies on the incorporation of the ketone 2 1 a-arylation of the ketone 149653.doc -31 - 201107311 awake or ketal at the 4-position (Fox et al., Jowrwa/ 〇 / ί/ze C/zewz'ca/iSockiy, 2000, /22, 1360). Corresponding self-contained starting materials 21 are commercially available or can be readily prepared by those skilled in the art, and a variety of acetals can be used, including the indicated ethylene ketals or other alcohols (including 1,3-propanediol, A ketal of sterols, ethanol and other alcohols. This chemistry is equally applicable to the production of unsubstituted alpha-aryl ketones 24. Process 6

Ar-X

twenty three

Pd2(dba)3. Xantphos Na(Of-Bu)

Wherein X = Br, I, the other alpha-aryl ketone can be prepared using the chemistry shown in stream 7, wherein bromine-containing dioxane or is generally used. The pyridinium hydrogen tribromide is used as a brominating agent to bromine tetrahydro-4H-pyran-4-one. The resulting a-bromo ketone can then be reacted with a Grignard reagent and after aryl migration, the desired a-aryl ketone 27 is obtained. Flow chart

As shown in the formula, 2-arylcyclopentanone 18 can be deprotonated with a strong base (such as LDA) to 149653.doc -32 - 201107311, and treated with alkyl cyanoformate to give ketoester 28, followed by 2 Reaction with methyl-2-thio pseudourea affords 2-amino-7-aryl-6,7-dihydrocyclopenta[4Π,3]oxazin-4(5//)-one 29. Compound 29 is hydrolyzed under acid catalysis to form 7-aryl-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4(3//,5/〇-dione 30 0 Larsen, JS; Christensen, L.; Ludvig, G.; J0rgensen, P. T.; Pedersen, EB; Nielsen, CJ Chem. Soc., Perkin / 2000, 3035-3035 °

Alternatively, 7-aryl-6,7-dihydrocyclopenta[e][i,3] can be obtained by reacting 2-arylcyclopentanone 18 with (gas carbonyl) isocyanate. evil. Qin _ 2, 4 (3 / /, 5 / /) - diketone 31 (all thin 9). Subsequent treatment of 7_aryl-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4(3//,5/〇-dione 31 followed by oxychlorination with aqueous ammonia

Phosphoric chlorination to give 2,4-dichloro-7-aryl-6,7-dihydro-5扒cyclopenta[d]pyrimidine 33 ° Scheme 9

Other ketones can be reacted with #(gas carbonyl) isocyanate in a manner similar to that described in Manchus 9 to give other oxazindione 35, oxazide diacetate 149653.doc • 33- 201107311 35 with ammonia The reaction is carried out to obtain a pyrimidinedione 36 (motherzed and then gasified to obtain an intermediate dichloride 37. In a similar manner, the ketal-protected ketone produced in the aliquot 6 can be used to carry out the chemical process to prepare a corresponding condensed product. Dichloropyrimidine (Zhuo "). Process 1 0

It is also possible to synthesize 2,4_digas_7_aryl-7,7-dihydro-5仄cyclopenta[d]pyrimidine 33. 4_gas_2 according to the route described in Julie/2. 6-Dimethoxypyrimidine 4〇 can be removed with a strong base such as n-butyllithium or 2,2,6,6-tetradecylpiperidine and quenched with allyl bromide to give 5-dipropyl Base 4-gas-2,6-dimethoxypyrimidine 41. Nencka, R.; Votruba, I.; Hfebabeck, H·; jansa, P;

Tloust'ova, E.; Horska, K.; Masojidkova, M.; Holy, a J from e 乂 C/zem. 2007, 50, 6016-6023. The compound can be reacted with a heart-styryl boronic acid (α-styrylborinic acid) in the presence of a palladium catalyst such as palladium (triphenylphosphine) palladium to give a compound of formula 42 which is available in Gibbs conditions (Grubbs) The ring-closing olefin metathesis reaction is carried out under conditions to form 2,4·dimethoxy-7-aryl-5/f-cyclopenta[d]pyrimidine 43. Grubbs 149653.doc •34· 201107311 Anti.ϋ·Handbook of Metathesis, 2QQ3, pp., Wiley·VCH. The double bond in compound 43 can be reduced to give 2,4-di-lactyl-7-aryl-6,7-dihydro-5//-cyclopenta[d]pyrimidine 44, followed by hydrolysis under acid catalysis The receiver was turbid with oxygen chlorination to obtain a medium. ‘ Process 1 2

Other members of the compound class of Technical Scheme 1 can be prepared as indicated in Figure 73. The benzonitrile is carboxylated, followed by simple reduction using a metal catalyzed (palladium/carbon or the like) to give a substituted β-amino ester 48. Condensation with acrylate gives intermediate 49, intermediate 49 can be alkylated on nitrogen to give the R substituent directly, or can be protected by p-nonylphenyl hydrazide using the indicated chemical procedure for subsequent removal Protect the group and introduce Rd. The intermediate 5 is then cyclized in the presence of a base (usually ΚΟί-Bu) to give the ketoester 5 丨 keto vinegar 51 and the veins condensed under the conditions to obtain the pyrimidinedione intermediate 52, followed by Chlorination can be carried out under standard conditions to give a di-gas 53. This di-vapor can be converted into a compound of the technical formula in the usual manner (see below). 149653.doc -35· 201107311 Process 1 3

Other members of the compound class of Technical Scheme 1 can be prepared as shown in the above. Acidification of the amine followed by alkylation with ethyl 4-bromobutyrate affords intermediate 56, intermediate 56 can be alkylated on nitrogen to directly obtain a substituent, or using the illustrated chemical process, It can be protected with p-methoxybenzoquinone to subsequently remove the protecting group and introduce Rd. The intermediate 57 is then cyclized in the presence of a base (usually ΚΟί-Bu) to give the β-ketoester 58. The β-ketoester 58 is condensed with urea under basic conditions to give the pyrimidinedione intermediate 59, which can then be gasified under standard conditions to give the dihydrate 60. This divaporate can be converted to the compound of Technical Scheme 1 in a conventional manner (see below). Process 1 4

149653.doc -36- 201107311

The dimethyl benzoyl group used to protect the nitrogen atom on the compound of structure 61 can be removed, for example, by the action of a strong acid (TFA as a cation scavenger in the presence of benzophenone) as shown in Manchu/5. The free amine is obtained, and then the free amine can be further derivatized, for example, by deuteration, sulfonation or alkylation in a conventional manner to prepare other compounds of claim 1. Similarly, if the amine position isomer 64 is not involved in the same chemical process, another compound of the first embodiment is obtained.

Process 15

Process 1 6

149653.doc •37- 201107311 Other analogs can be prepared by the chemical processes detailed in Light 7-7. The vinegar is formed from commercially available base acid 67 under Fisher conditions, followed by alkylation of the alcohol under the catalysis of silver oxide (1). The olefin is reduced and cyclized to give β-ketoester 71. The pyrimidinedione is formed together with KOi-Bu and urea, followed by gasification with P0C13 to give the divaporate 73, which can be converted to the compound of the first embodiment as described in the above. Process 17

Other analogs can be prepared using the chemical procedures shown in the section. The pyrimidine-2,4,6-triol was reacted with P0C13 in DMF to give chlorinated aldehyde 75. The aldehyde is protected and then reacted with a Grignard reagent to produce a two vapor reagent 77. After the hydrolysis removal of the protecting group and the reduction of the aldehyde to the alcohol, the tetrahydrofuran ring can be closed under the action of lead tetraacetate to obtain a substituted divaporate 80, which can then be used according to the method described below. To prepare the compounds of other technical scheme 1. Process 1 8

149653.doc • 38 · 201107311

2,4-Chloro-7-aryl-6,7-dihydro-5i/cyclopenta[d] pulverized 81 selectively reacts with a primary amine and a secondary amine to give a 2-amino derivative 82, can be coupled with aniline 4 under heating to form the title compound 83 (streaming. The coupling can be carried out under acidic conditions (for example using acetic acid) or under basic conditions (for example using sodium hydride). Under metal catalysis under conditions known in the literature, for example using palladium Xantphos catalyst, in strong bases (Na〇/_Bu) or

Coupling is accomplished in the presence of Na2C〇3 in an aqueous cosolvent mixture (usually THF/water or dioxane/water).

Process 1 9

Other technical solutions can be prepared by formulating the intermediate 86 by condensing the condensed oxime diamine and aniline α in the manner described above (flow 20). For example, removal of the protecting group of the ketal with an aqueous solution of the acid produces a ketone which is an intermediate which is highly suitable for the production of other compounds. The ketone can be directly condensed (reductive alkylation) with an amine under reducing conditions to prepare a substituted amine compound 89. Alternatively, the hydrazine reagent (such as NaBH^LiA) can be used to reduce 嗣' to give an alcohol. The alcohol 90 can be activated, for example, by hydrazine, followed by nucleophile replacement including thiol, 3 nitride or other nucleophile. Oxygen 149653.doc -39- 201107311 thiol, made in Asia; E wind and shout. By reducing the azide, the amine amine can be easily prepared to further calcination to produce the other compound of the first embodiment. Process 20

Another method of preparing the analog of claim 1 is described in Manz. Further, with acid 7 6 as a starting material, a chain phenyl diterpene was added to obtain an intermediate 92. Removal of the protecting group provides the ketoaldehyde 93 which can be closed by sequential reductive alkylation to form a substituted pyrrolidine 94. The amine can be introduced directly into the desired Rd substituent' or as described in the scheme, an amine incorporating a protecting group (including 4-decyloxybenzyl) can be used. According to the method herein, the divaporate thus obtained can be converted into the compound of the first embodiment. The 4-nonoxyphenyl fluorenyl group can then be removed by methods known to those skilled in the art, such as the use of phenyl ether containing TFA as a cation scavenger, followed by a known method 149653.doc •40 - 201107311 Alkylation, deuteration or sulfonation to prepare other analogs. Process 21

Other pyrimidine dichlorides prepared using the above methods or other methods known in the art can be converted to other analogs of Scheme 1 in the general manner as shown in Scheme 22. The pyrimidine di-vapor is reacted with an amine to obtain a chloride 99 corresponding to the structure D-E as described in the first embodiment, wherein the linkage structure D-E is activated to a replaceable gas group at the bond of the ABNH fragment. The title compound of Technical Scheme 1 is then prepared by condensing chloride 99 with aniline ABNH2 according to the previously described method (浚茗/9). Process 22

The racemic target, the mediator enantiomer (涊小d), can be isolated by a palm method known to those skilled in the art. This is shown below in the % pent[d]pyrimidine system, J, but is equally applicable to other external processes described herein.

N-^ RivN-Rs

Another method for producing the compound of the technical scheme i is shown in 6 R1 Coffee Length 23. Commercially available 4-chloro-2,6-dimethoxypyrimidine 1〇1 can be removed with butyl lithium or tetramethyl methacrylate, followed by allylation to give a protected core 1〇2. Suzuki coupling with a phenyl group-acid under domain formation affords dilute 103' which can be effectively cyclized by ring closure metathesis under Gibbs π catalyst using standard conditions. The olefin can then be reduced to give intermediate 105. The removal of the protecting group and chlorination under the conditions of (quasi), (iv) another way of preparing the two gasification 106, can be converted to the compound of the first embodiment using the chemical process shown in the streamer 22. Process 23

Η2

1. HCI 2- P〇CI3 OMe Gibbs Π DCE ^ 80-9CTC or MeO*

Pd/C10% EtOAx

Separation of the racemic label by a sexual method can be carried out by a person skilled in the art, 149 149 653 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 This is shown below in the cyclopenta[d]pyrimidine series, but is equally applicable to other racemic compounds described herein. Process 2 4

It is an abbreviation for high pressure liquid chromatography in this paper. "lC_MS" is a high pressure liquid chromatography chromatographed using a mass spectrometry detector as defined by HPLC. HPLC solvent conditions: When described as being carried out under "standard conditions", the sample was dissolved in methanol (丨mg/mL) and was run using a gradient program at a solvent flow rate of 〇mL/min. Reverse phase preparative HpLC: When described as being carried out under standard conditions, the sample (about 20 mg) is dissolved in methanol (1 〇 mg/mL) and on a 3 〇 mm x 100 mm Waters-Atlantis S5 column, 10 The gradient was dissolved in a minute gradient from buffer A/〇 to 1 〇〇0/〇 buffer B (buffer A=10% CH3OH/90% water/0.1% TFA and buffer b=90〇/〇)

MeOH/10% water/〇.1% TFA) was purified at 4 mL/min. Proton NMR spectroscopy was obtained on a Bmker-400 or 500 spectrometer. The information is related to the lock solvent. The examples are provided to aid in the further understanding of the invention, and the specific materials, materials, and conditions of the invention are intended to further illustrate the particular embodiments of the invention and not to limit the scope of the invention. Synthetic intermediate

Preparation A 149653.doc -43· 201107311 4-(4-Gas-1H-imidazol-1-yl)-3-methoxyaniline

CI

Intermediate AC1) 4-Gas-1-(2-decyloxy-4-nitrophenyl)-1Η-imidazole

C1-O will be 4-gas-1H-micron. Sit (5.0 g, 48.8 mmol), 1-Gas-2-methoxy-4-nitrobenzene (9.15 g, 48.8 mmol) and flaky potassium hydroxide (2.74 g, 48.8 mmol) in anhydrous DMSO (50 mL) The mixture in the mixture is at 8 〇. Heat under the arm for 20 hours. The reaction mixture was cooled to room temperature and poured into 8 mL of water with vigorous stirring. The resulting yellow-orange precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The coarse wet solid was transferred to a 丨L conical flask. Anhydrous ethanol (250 mL) was added to the flask and the resulting suspension was heated until all solids dissolved. The clear solution was cooled to room temperature and the desired product slowly crystallized. After 2 hours, the crystalline solid was collected by vacuum and washed with (iv) q w fresh ethanol. The solid was dried under high vacuum to give 4-chloro-1-(2-methoxy-4-[s. LC-MS (M+H)+=254 n 'η •0. H NMR (500 MHz, CDC13) δ ppm 7.94-8.01 (m, 2 H) 7.76 (d ri ^ , y (d, J-1.53 Hz, 1 H) 7.45 (d, 7=8.55 Hz, 1 H) 7.21 (d J=\ 1.53 Hz, 1 H) 4.02 (s, 3 H).

Preparation A M4-gas-1H-imidazolyl)_3_methoxyaniline 149653.doc -44- 201107311

325 mesh iron powder (4.6 g, 82 mmol) was added to the mixture containing 4-chloro-1-(2-methyllacyl-4-nitrocarbyl)-1 oxime-mole (5.2 g, 20.5 mmol), absolute ethanol A 5 〇〇 mL round bottom suspension of a mixture of (100 mL) and glacial acetic acid (50 mL). A water-cooled reflux condenser was attached to the flask and the heterogeneous mixture was heated to 1 °C for 30 minutes with vigorous stirring. The reaction mixture was cooled to room temperature and added to a cooled and stirred 3 M NaOH solution (291 mL). The resulting mixture was poured into a sep. funnel and extracted with EtOAc (3×250 m). The combined organic layers were dried with EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS (M+H)+ 224.0. NMR (500 MHz, CDC13) δ ppm 7.47 (d, /=1.22 Ηζ,1 Η) 7.00 (d, 7=8.24 Hz, 1 H) 6.99 (d, J=1.53 Hz, 1 H) 6.32 (d, 7 =2.44

Hz, 1 H) 6.29 (dd, /=8.24, 2.44 Hz, 1 H) 3.88 (br. s., 2 H) 3.78 (s, 3 H).

Preparation AA 4-(4-cyano-1H-imidazol-1-yl)-3•nonylaniline

NC

NH2 intermediate AA(1) cyano-1 -(2-methoxy-4-nitrophenyl)-ΐη-imi

-45· 149653.doc 201107311 To 1H-imidazole-4-carbonitrile (300 mg, 3.22 mmol) and 4-fluoro-3-indolyl nitrobenzene (552 mg, 3-22 mmol) in DMF (volume: 6446 μΐ Κ2〇03 (891 mg, 6.45 mmol) was added to the solution. The resulting mixture was brought to 120 ° C and stirred overnight. The reaction mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) -1 Η-imidazole-4-indene nitrile (698 mg, 2.86 mmo yield 89%). LC-MS (Μ+Η)+=245·〇. ΗΝΜΚ_(500 ΜΗζ,Μβ〇Ζ))δρρηι8·30-8.34 (1 Η), 8.19- 8.23 (1 Η), 8.09-8.12 (1 Η), 8.00-8.05 (1 Η), 7.71-7.79 (1 Η ), 4.02-4.10 (3 Η). Preparation of ΑΑ 4-(4-cyano-1H-imidazol-1-yl)-3-decyloxyaniline

Add acetic acid to a solution of bis(2. methoxy-4-stone phenyl)-im °-4-acetonitrile (689 mg, 2.82 mmol) in EtOH (ratio: 2, volume: 15 mL) Ratio: 1.000, volume: 7.50 mL) and iron (630 mg, 11.29 mmol). The resulting mixture was allowed to reach 1 ° C and allowed to stand for 2 hours. The reaction was then diluted with water and brought to pH 8 by addition of 1N aqueous sodium hydroxide. This mixture was extracted with EtOAc (3 < 5 mL). The combined extracts were washed with water (5 mL) brine brine LC-MS (M+H)+ = 215.0.

Preparation B I49653.doc •46· 201107311 3-Fluoro-4-(3-methyl-1H-1,2,4-trian-1-yl)aniline

Intermediate B(l) 1-(2-fluoro_4_nitrophenyl)-3-methyl_ih-1,2,4-triazole

No2

Will be 3-methyl-1H-1,2,4-three. a mixture of (15_0 g, 181 mmol), 1,2-difluoro-4-nitrobenzene (28_7 g' 181 mmol) and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) at 8 Heat at 〇 ° C for 48 hours. The reaction mixture was cooled to room temperature and poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed sequentially with water (5 mL) and brine (100 mL). The organic layer was dried <RTI ID=0.0>: </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> Combine the purely soluble fractions of the less polar positional isomers and concentrate to give 1-(2-fluoro-4-nitrophenyl)_3_methyl-1H-1,2,4-tris as an off-white solid Azole (7.2 g, 30.8 mmol, yield 17%). The pure fractions of the more polar regioisomers are combined and concentrated to give 1-(2-fluoro-4-nitrophenyl)-5-mercapto-1H-1,2,4- Triazole (6.23 g, 28.0 mmo yield 15%). ^(2-Fluoro-4_nitrophenyl)_3_indolyl-1H-1,2,4-triazole data: LC-MS (M+H)+=223.1. NMR (500 MHz, CDC13) δ ppm 8.73 (d, «7=2.7 Hz, 1 H), 8.15-8.26 149653.doc -47- 201107311 (m,3 Η), 2.53 (s,3 Η). Preparation Β 3-|L-4-(3 -indolyl-1Η-1,2,4_tris.-1-yl)aniline

Add 10%/carbon (2.50 g, 23.5 mmoj.) to 1-(2-fluoro-4-nitrophenyl)·5-methyl-1H-1,2,4-tris under a nitrogen atmosphere Ixazole (15.0 g, 67.5 mmol, from a cooled (ice-water bath) solution of the preparation a step in methanol (4 mL). The flask was repeatedly vented and rinsed with hydrogen (double balloon). The temperature was raised to room temperature and stirred under a hydrogen atmosphere for 72 hours. The vessel was then purged with nitrogen. The reaction vessel and its contents were cooled (ice water bath) and another portion was added. palladium/carbon (2.50 g, 23 5 mmol). The flask was repeatedly vented and flushed with hydrogen (double balloon). The resulting mixture was warmed to room temperature and stirred under a hydrogen atmosphere for 6 hours. The vessel was then purged with nitrogen. Celite®) Filtration. The reaction vessel and Celite® were washed with fresh methanol. The combined filtrate was concentrated in vacuo. The residue was dried under high vacuum overnight to afford 3 _______ Monoazol-1-yl)aniline (12.1 g, 63〇mm〇1, yield 93%). (M+H)+ 193.2 〇Ή NMR (500 MHz, CDC13) δ pp m 8.31 (d, */=2.4 Hz, 1 H), 7.47 (t, J=8.7 Hz, 1 H), 6.47-6.58 (m5 2 H), 3.97 (br. s·, 2 H), 2.48 ( s, 3 H).

Preparation C 3-1-4-(5-methyl-111-1,2,4-triazol-1-yl)aniline 149653.doc -48- 201107311

Intermediate c(i) 1_(2Fluoro_4_nitrophenyl)-5-mercapto-1H-1,2,4-triazole

3-methyl-1H-1,2,4-triazole (15.〇g, 181 mm〇1), 1&gt;2_difluoro-4-nitrost (28.7 g, 181 mm〇i) and carbonic acid A mixture of sodium hydride (152 g, 181 mmol) in DMSO (100 mL) was warmed at 8 (rc) for 48 hours. The reaction mixture was cooled to room temperature and poured into water (8 mL). The mixture was extracted with water (5 mL) and brine (100 mL). The crude reaction mixture was purified by 〇0 / EtOAc / hexanes &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; (2-Fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol, yield 17%). Combines the more polar regiois Purely dissolving and concentrating to give 1_(2-fluoro-4-cholythylphenyl)-5-methyl-1H-1,2,4-tris-sodium (6.23 g, 28.0 mmol' yield 15 as a white solid. %). 1-(2-Fluoro-4-nitrophenyl)-5-fluorenyl- Information on 1H-1,2,4-triazole: LC-MS (M+H)+=223.1. 4 NMR (500 MHz, CDC13) δ ppm 8.18-8.24 (m, 2 Η) 8.04 (s, 1 Η 7.69-7.78 (m,1 Η) 2.47-2.53 (m,3 H). 149653.doc -49· 201107311 Preparation c

Add 1%% bar/carbon (1.5 g, 14.1 mmol) to ι_(2-fluoro-4-nitrophenyl)_5_ decyl_1H-1,2,4- under a nitrogen-fluorine atmosphere Triazole (3.7 g, n mm 〇 1) was taken in a cooled (ice water bath) solution in methanol (200 mL). The flask was repeatedly vented and flushed with hydrogen (double balloon). The resulting mixture was warmed to room temperature and stirred under a hydrogen atmosphere for 18 hr. The vessel was then purged with nitrogen. The crude reaction mixture was filtered through a pad of Celite®. Clean the reaction vessel and Celite® with fresh sterol. The combined filtrate was concentrated in vacuo. The residue was dried under high vacuum to give 3-fluoro-4-(5-methyl-1H-1,2,4-triazol- yl) phenylamine (3.14 g, yield 91%). ). LC-MS (M+H)+ 193.1. 4 NMR (500 MHz, CDC13) δ ppm 7.91 (s, 1 H) 7.14 (t, ^=8.55 Hz, 1 H) 6.43-6.53 (m, 2 H) 4.04 (br. s., 2 H) 2.36 ( s, 3 H) 〇

Preparation D 3-methoxy-4-(3-methyl-111-1,2,4-tris. sit-1-yl)aniline

Intermediate D(l) 1-(2-methoxy-4-nitrophenyl)_3_methyl_111_1,2,4_triazole 149653.doc -50- 201107311

No2

3-mercapto-1H-1,2,4-triazole (5.0 g, 60.2 mmol), 1-chloro-2-indolyl-4-nitrobenzene (11.3 g, 60.2 mmol) and flakes A mixture of (3·4 g, 48·1 mmol) in anhydrous DMSO (50 mL) was heated at 80 ° C for 6 hours. The reaction mixture was cooled to room temperature and poured into 800 mL of water with vigorous stirring. The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organics were washed with EtOAc EtOAc m. The crude residue was purified using EtOAc (EtOAc (EtOAc:EtOAc) 4-triazole (3.7 g, yield 26%). LC-MS (Μ+Η)+=235·2.

Preparation D 3-methoxy-4-(3-methyl-1Η-1,2,4-triazol-1-yl)aniline

Add 10% palladium on carbon (1.2 g) to 1-(2-decyloxy-4-stone osylphenyl)-3-indolyl-1H-1,2,4-three-zero (3.7) under nitrogen atmosphere g, 12.7 mmol) was dissolved in a cooled (ice water bath) solution in methanol (250 mL). The flask was repeatedly vented and flushed with hydrogen (double balloon). The resulting mixture was warmed to room temperature and stirred under an argon atmosphere for 18 hours. Purge with nitrogen. The crude reaction mixture was filtered through a pad of Celite®. The reaction vessel and plug were washed with methanol. The filtrate was concentrated in vacuo. The residue was dried under high vacuum overnight to give 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline as a reddish solid (2.44 g, yield 94%). LC-MS (M+H)+ 205.2 〇ipi NMR (500 MHz, CDC13) 149653.doc -51- 201107311 δ ppm 8.35 (s, l Η) 7.36 (d, J=8.55 Hz, 1 H) 6.29-6.34 (m, 2 H) 3.80 (s, 3 H) 2 46 (s, 3 H). Preparation ΏΏ 3 -Methoxy-4-(5-mercapto-1H-1,2,4-triazol-1-yl)aniline

The intermediate C(l) is reacted with Na〇Me in DMF to give 1-(2-methoxy-4-nitrophenyl)-5-methyloxime^, triazole, via Fe and gasification. Ammonium reduction gave the title compound. LC_MS (M+H) + 205.1.丨H NMR (500 MHz, Μ, Ί^-d) δ ppm 7.90 (1 H, s), 7.05 (1 H, d /=7.93 Hz), 6.27-6.34 (2 H, m), 3.91 (2 H , br. s.)5 3.73 (3 H,s), 2.29 (3 H,s).

Preparation E 3 —Methoxy-4·(4-indolyl-1H-imidazol-1-yl)aniline

Intermediate E(l) 1-(2-decyloxy-4-stone phenyl)-4-mercapto-1H-imidazole

Will be 4-methyl-1H-mi. Sit (18·0 g, 53.5 mmol), 1-Gas-2-indoleoxy 4-nitrobenzene (10.0 g '53·5 mmol) and potassium hydroxide (4.5 g, 8〇3 mmol) in DMSO The mixture in (50 mL) was heated under litre for 24 hours. 149653.doc •52- 201107311 The reaction mixture was cooled to room temperature and poured into 1000 mL of water. The aqueous mixture solution was extracted with dioxane (3 X 250 mL). The combined organic extracts were washed with brine, dried over sodium s s s s s s s s s s s s s s The crude reaction mixture was purified to give 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, yield 20%). . LC-MS (M+H)+=234.1. 4 NMR (500 MHz, CDC13) δ ppm 7.97-8.00 (m,1 Η) 7.93-7.97 (m,2 Η) 7.45 (d, "7=8.85 Hz, 1 Η) 7.02 (s,1 Η) 4.02 (s,3 Η) 2.35 (s, 3 H).

Preparation E 3-methoxyl_4·(4-mercapto-1H-imidazol-1-yl)aniline

10% palladium on carbon (250 mg) was added to 1-(2-decyloxy-4-sinylphenyl)-4-mercapto-1H-0 m under a nitrogen atmosphere. Sit (2.56 g, 11 · 0 mmol) in a cooled (ice water bath) solution in methanol (150 mL). The flask was repeatedly vented and flushed with hydrogen (double balloon). The resulting mixture was warmed to room temperature and stirred under a hydrogen atmosphere for 18 hr. Purge with nitrogen. The crude reaction mixture was filtered through a pad of Celite®. The reaction vessel and plug were washed with methanol. The sputum is concentrated in vacuo. Vacuum-drying of the residue separator was added to 3-methoxy-4-(4-methyl-1Η-imidazol-1-yl)aniline (2.25 g, yield 100) %). LC-MS (M+H)+ 204.1. 4 NMR (500 MHz, 149653.doc -53·201107311 c〇Cl3) δ ppm 7.69 (s9 1 Η ) 7.01 (d, J=8.55 Hz, 1 H) 6 82 (s, 1 H) 6.33 (d, j = 2.14 Hz, 1 H) 6.30 (d, "7=8.55 Hz ί", 3-78 (s, 3H) 2.33 (s, 3H). '

Preparation EE 3-decyloxy-4·(4-difluoroindolyl-1H-imidazol-1-yl)aniline

Intermediate EE(1) 4-(difluoroindolyl)-lH-imidazole

Deoxyfluor was added to the hydrazine-trityl-1H-imidazole-4-furaldehyde in dioxane at 〇 ° C and stirred for 3 days. The product was then treated with 1:5 Ac〇H/Hci overnight at ambient conditions to give 4•(difluorodecyl 1H-imidazole.

Preparation EE 3-methoxy-4-(4-difluoroindolyl-1H-imidazol-1-yl) strepamine

The intermediate EE(1) was reacted as described for Preparation E to give the desired preparation *EE ° LC-MS (M+H) + 240.2 〇1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (s, 1 Η) 7.93 (s,1 H), 7.48 (d, J=8.4 Hz, 1 H) 7.19-6.88 (m,3 H) 3.81 (s,3 H) 〇149653.doc -54, 201107311

Preparation F-methoxylamine 4-(3-chloro-111-1,2,4-tri'&gt;spin-1-yl)_3

CI

Nh2 intermediate F(l) oxazol-1-yl)-5-nitrophenol

3-Oxo-1Η-1,2,4-triwax (2.76 g '26.7 mm〇i), u_2_decyloxy-4-nitrobenzene (5_0 g, 26.7 mmol), flaky potassium hydroxide (1) A mixture of 496 g, 26.7 mmol) and DMS hydrazine (25 mL) was heated in a sealed reaction vessel at 100 ° C for 24 hours. The reaction was cooled to room temperature and other portions of 3- s-1H-1,2,4-triazole (1.38 g, 〇. 5 eq.) and potassium hydroxide (75 g) were added. Re-service, seal the reaction bar and reheat to 11 〇. Oh, maintain 24

hour. The resulting mixture was cooled to room temperature and poured into 5 mL of water. The aqueous mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with brine <RTI ID=0.0> The crude residue was purified using silica gel chromatography (0-5% MeOH/chloroform, 144 min gradient gradient, 25 <RTIgt; 5-)-5-nitrophenylhydrazine (0.924 g, 3.84 mmol, yield 14.4%). LC-MS (M+H)+ = 241.0. NMR (500 ΜΉζ, CDC13) δ ppm 11.97 (br. s·,1 Η) 9.24 (s, 1 Η) 7.90-7.95 (m, 1 Η) 7.89 (d, /=2.44 Hz, 1 H) 7.84 (dd , 7=8.85, 2.44 Hz, 1 H) ° 149653.doc •55· 201107311 Intermediate F(2) 3-Gas-1-(2-methoxy-4-nitrophenyl)-1 Hl,2 4-triazole

Add moth (0.860 mL, 13.82 mmol) to 2-(3-gas-1H-1,2,4-dis-sul-1-yl)-5-de-ylbenzene (Ig 33 g, 5.53) Methyl), a mixture of potassium hydroxide (0.388 g, 6.91 mmol) and DMSO (25 mL). The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water (25 mL EtOAc)EtOAc. The combined extracts were washed with EtOAc (EtOAc)EtOAc. The crude residue was purified using a hexane column chromatography (EtOAc EtOAc/EtOAc) The pure fractions were combined and concentrated to purified crystals crystals crystalsssssssssssssssssssssssssssssssssss , yield 65.6%). LC-MS (M+H)+ = 255.0. A NMR (500 MHz, CDC13) δ ppm 8.35 (s, 1 Η) 7.36 (d, /=8.55 Hz, 1 Η) 6.29-6.34 (m, 2 Η) 3.80 (s, 3 Η) 2.46 (s, 3 H).

Preparation F 4-(3-Gas-1H-1,2,4-triazol-1-yl)-3-nonanoylaniline

Add water (8 mL) and dioxane (8 mL) to a 2-mL 1-(2-methoxy-4-carbophenyl)-iH-l,2,4-three-dose in a 20 mL vial (0.900 g, 3.53 149653.doc • 56·201107311 mmol) in a mixture with sodium sulfide (1.379 g ' 17.67 mmol). The vial was capped and heated at 70-80 °C for 24 hours. The mixture was cooled to room temperature, poured into water (300 mL) and extracted with EtOAc (2×l 50 mL). The combined organic layers were washed with EtOAc (EtOAc m. 3-Methoxyaniline (577 mg, 73%). LC-MS (Μ+Η) + 225.1.

Preparation FF 6-(4-Ga-1Η-imidazol-1-yl)-5-methoxypyridine-3-amine

Intermediate FF(1) 2-(4-Chloro-1H-imidazol-1-yl)-3-decyloxy-5-nitroacridine

Will be 4-gas-1Η-σ meters. Sit (2.72 g' 26.5 mmol), 2-chloro-3-methoxy-5-nitropyridinium (5.0 g, 26.5 mmol) and flaky KOH (1488 g, 26.5 mmol) in anhydrous DMSO (25 mL) The mixture was heated at 8 (TC for 5 hours. The reaction mixture was cooled to room temperature and poured under vigorous stirring into 1 mL of water. The mixture was stirred at room temperature for 16 hours. By vacuum transition, coarse sintering was used. The glass funnel was used to collect the precipitate. The solid was dried under high vacuum for 24 hours to give 2-(4-H-1H-imidazol-1-yl)-3-decyloxy-5-nitron ratio as a light brown solid. 5.22 g, 20.50 mmol, yield 77%). LC-MS (M+H)+= 255.0. 'H NMR (500 MHz, DMSO 〇δ ppm 8.94 (d, 149653.doc -57-201107311 2·44 Hz , 1 Η) 8.51 (d, &gt;1.83 Hz, 1 Η) 8.42 (d, &gt; 2.44 Hz 1 H) 8.02 (d, ·7=1_83 Hz, 1 H) 4.12 (s, 3 H).

Preparation FF 6-(4-Fluoro-1H-methane. Sodium-l-yl)-5-decyloxy-bite-]-amine

Add 3 25 mesh iron powder (2.19 g, 39.3 mmol) to 2 (4chloro_1H-imidazol-1-yl)-3-decyloxy-5-nitropyridine (5.0 g, 19.64 mmol), anhydrous A mixture of a mixture of ethanol (50 mL) and glacial acetic acid (20 mL). Water-cooled back to the SlL condenser was attached to the flask&apos; and the heterogeneous mixture was heated to 100 °C with a drop of sandalwood for 30 minutes. The reaction mixture was cooled to room temperature and then neutralized after being added to a cooled and vigorously stirred 5 M NaOH solution. The resulting mixture was poured into a sep. funnel and extracted with EtOAc. The combined organic layers were dried with sodium sulfate, filtered andlulululululululululululululululululululululu . LC-MS (M+H)+ 225.1. H NMR (500 MHz, CDC13) δ ppm 8.06 (d, J = 1.83 Hz, 1 H) 7.53 (dd, 7=13.28, 1.98 Hz, 2 H) 6.70 (d, /=2.44 Hz, 1 H) 3.90 (s, 3 H) 3.86 (br. s., 2 H).

Preparation FFF 2-Fluoro-5-methoxy-4-(3-mercapto-1H-1,2,4-triazol-1-yl)aniline

F 149653.doc -58 - 201107311 Intermediate FFF(l) 1-(5-fluoro-2-methoxy-4-nitrophenyl)_3_indolyl-1H_1,2,4-triazole

3-mercapto-1H-1,2,4-triazole (2.20 g, 26.4 mmol), 1,5-difluoro-2-indolyl-4-nitrogen (5·〇〇g, 26.4 mmol And a mixture of potassium carbonate (3.65 g, 26.4 mmol) in anhydrous EtOAc (50 mL). The reaction mixture was cooled to room temperature and poured into 5 mL of water / 10 mL brine. The aqueous mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with EtOAc EtOAc. Purification of the crude reaction mixture using hydrazine column chromatography (50% EtOAc/hexanes) afforded 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-indolyl-1H-1. 2,4-triazole (1.24 g, yield 18%). LC-MS (Μ+Η)+=253·2. NMR (500 MHz, CDC13) δ ppm 8.95 (s, 1 H) 8.00 (d, /=11.60 Hz, 1 H) 7.80 (d, /=6.10 Hz, 1 H) 4.09 (s, 3 H) 2.50 (s , 3 H).

Preparation FFF 2-Fluoro-5-decyloxy_4_(3-mercaptotriazol-1-yl)aniline

10% palladium on carbon (0.523 g, 4.92 mmol) was added to 1-(5-fluoro-2-indolyl-4-nitrophenyl)-3-methyl-1 oxime-1 under a nitrogen atmosphere. 2,4-triazole (1.24 149653.doc -59- 201107311

g ' 4.92 mmol) was dissolved in a cooled (ice water bath) solution in methanol (loo mL). The flask was repeatedly vented and flushed with hydrogen (double balloon). The resulting mixture was warmed to room temperature and stirred under a hydrogen atmosphere for 18 hr. The vessel was then purged with nitrogen. The crude reaction mixture was filtered through a pad of Celite (CeUte®). The reaction vessel and plug were washed with fresh methanol. The combined filtrate was concentrated in vacuo. High vacuum drying residue spacers to give 2_fluoro_5_decyloxy_4_(3·indolyl-1H-1,2,4-triazol-1-yl)aniline Q 〇5 as a gray solid g, yield 96 〇 / 〇). LC_MS (M+H) + 223.1. NMR (500 MHz, CDC13) δ ppm 8.46 (s,

1 Η) 7.39 (d, 7=11.29 Hz, 1 H) 6.44 (d, J=7.63 Hz, 1 H) 3.89 (br. s., 2 H) 3.83 (s, 3 H) 2.47 (s, 3 H 〇Preparation G 2,4-diqi-7-phenyl-6,7-dihydro-5孖-cyclopenta[d]pyrimidine

Intermediate G(l) cyclopentenylbenzene

Solution (49.7 mL, cooled to 0. (: Add [] to this solution. Stir the reaction mixture at room temperature], add ice (20 g), then add to the desertified phenyl lock in the scale Add thF (300 mL) to 3. 〇m mmol). Cool to % pentanone (13.23 mL, 149 mmol). Stir in the chamber for 30 minutes' and then under reflux for 2 hours Ο 149 149653.doc -60- 201107311 HC1 until the temple dissolves. The product was extracted by an assay. The combined ether layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj )+=145·1.4 NMR (500 MHz, CDC13) δ ppm 7.48 (2H, d, J=7.3 Hz), 7.35 (2H, t, /=7.8 Hz), 7.22-7.27 (1H, m), 6.22 (1H, t, J=2.1 Hz), 2.70-2.80 (2H, m), 2.52-2.64 (2H, m), 2.01-2.12 (2H, m). Intermediate G(2) 2-stylcyclopentanone

A mixture of 30/〇 ruthenium peroxide (23 mL, 149 mmol) and 85% formic acid (loo mL, 2619 mmol) was heated at 4 ° C for 15 minutes. The mixture was carefully added to cyclopentenylbenzene (21.49 g, 149 mmol) and the resulting two-phase system was vigorously stirred at room temperature for 4 hours. An exothermic reaction was initially observed. At the end of the agitation, the solution became homogeneous. The reaction mixture was carefully quenched with saturated aqueous sodium bicarbonate. The product was extracted with diethyl ether. The combined test layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the product was purified by EtOAc EtOAc (EtOAc) LC-MS (M+H)+=161. 1h NMR (500 MHz, CDC13) δ ppm 7.38 (1Η, t, J=7.3 Hz) 7 3〇-7.35 (2H, m), 7.19 (2H, d, /=7.3 Hz), 3.28-3.37 (1H m ) 2.71 (1H, td, J-A.6, 2.7 Hz), 2.58-2.63 (1H, m), 2 43-2 55 149653.doc • 61 - 201107311 (1H, m), 2.29 (1H, ddd, 7=19.0, 10.5, 9.0 Hz), 2.07-2.21 (1H, m), 1.88-1.99 (1H, m) ° Intermediate G(3) 2-Sideoxy-3-phenylcyclopentane decanoic acid B ester

To a solution of diisopropylamine (6.62 mL, 46.8 mmol) in thF (200 mL) was added &lt;RTI ID=0.0&gt;&gt; The solution was stirred at -78 °C for 30 minutes and treated with a solution of 2-phenylcyclopentanone (5 g, 3 1.2 mmol) in 50 mL of anhydrous THF. After stirring at -78 °C for 30 minutes, ethyl cyanoformate (3.36 mL, 34.3 mmol) was added to the mixture. The resulting solution was warmed to 25 ° C over 3 hours with stirring. The reaction mixture was quenched with EtOAc (EtOAc m. Ethyl cyclopentanecarboxylate (5.3 g ' 22.82 mmol, yield 73%). LC-MS (M+K)+ = 273.2. *H NMR (500 MHz, CDC13) δ ppm 7.32-7.39 (2H, m), 7.25-7.31 (1H, m), 7.19-7.25 (2H, m), 4.18-4.32 (2H, m), 3.29-3.55 (2H, m), 1.87-2.62 (4H, m), 1.28-1.39 (3H, m) ° Intermediate G(4) 2-Amino-7-phenyl-6,7-dihydrocyclopenta[ e][13]oxazine_4(5 ugly)-ketone

149653.doc -62- 201107311 2-Methyl-2-thiopyrazine sulfate (1.336 g, 9.61 mmol) was dissolved in water (10 mL) and EtOAc (1. 2-Phenoxy 3-phenylcyclopentanecarboxylate (2.03 g, 8.74 mmol) was added under stirring and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and diethyl ether, and dried over anhydrous sodium sulfate to afford 2-amino-7-phenyl--6,7-dihydrocyclopenta[e][ l,3]oxazine·4(5//)-one (1.22 g, 5.35 mmol, yield 61.2%). LC-MS (M+H)+=229.1. 4 NMR (500 MHz, dimethylsulfoxide-do) δ ppm 7.57-7.85 (2H, m)5 7.08-7.47 (5H, m), 4.25-4.38 (1H , m), 1.72-2.73 (3H, m), 1.09-1.31 (1H, m) 〇 intermediate G(5) 7-phenyl-6,7-dihydrocyclopenta[e][l,3] Oxazine-2,4(3i/,5/〇-dione

Dissolving 2-amino-7-phenyl-6,7-dihydrocyclopenta[e][l,3]oxazine-4 (5/〇-one (900 mg, 3.94 mmol) in agitation with stirring 3 Μ Μ HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl Drying, concentration in vacuo, and purification by column chromatography to give 7-phenyl-6,7-dihydrocyclopenta[e][i,3]oxazine-2,4 (3//, 5//)-dione (350 mg, 1.527 mmol, yield 38.7%) 〇LC-MS (M+H)+=230.0 0 'H NMR (500 MHz, 149653.doc -63·201107311 CDC13) δ ppm 8.34 (1H, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18 (2H, d, J=7.3 Hz), 4.20 (iH, t, /=7.6

Hz), 2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m). A solution of 2-phenylcyclopentamine (19.995 g, 125 mmol) and N-(gas-carbon)isocyanate (23.70 g '225 mmol) was stirred at 58 ° C for 1 hour and at 1 30 ° C Mix for 45 minutes. The resulting tarrified reaction mixture was dissolved in ethyl acetate and neutralized with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The product was purified by hydrazine gel column chromatography to give 7-phenyl-6,7-dihydrocyclopenta[e][1,3]carbo-2,4 (37/) as a brown solid. , 5//)-dione (3.75 1 g, 16, 36 mmol, yield 13%). LC-MS (M+H)+ = 230.0. NMR (500 MHz, CDC13) δ ppm 8.34 (1Η, br s), 7.35 (2H, t, J=7.3 Hz), 7.27-7.32 (1H, m), 7.18 (2H, d, J=T.3 Hz ), 4.20 (1H, t, J = 7.6 Hz), 2.82-2.91 (1H, m), 2.61-2.79 (2H, m), 2.11-2.21 (1H, m). Intermediate G(6) 7-phenyl-6,7-dihydro-17/-cyclopenta[d]pyrimidine-2,4(3/i,5//)-dione

7-Phenyl-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4(3//,5//)-dione (3.751 g ' 16.36 mmol) in concentrated 149653.doc •64·201107311 of ammonia water (80 mL, 16.36 mmol) was heated in a 350 mL high pressure flask for 5 hours. The solvent was removed in vacuo to give 7-phenyl-6,7-dihydro-l/ί-cyclopenta[d]D as a brown solid _ 2,4 (3 / /, 5 good) - _ (3.73 g ' 16.34 mmol, yield 1%). [〇MS (Μ+Η)+=229·1. 4 NMR (500 MHz, dimethyl sulfoxide-do) δ ppm 7.34 (2H, t, J=7.5 Hz), 7.26 (1H, t3 J=7.3 Hz ), 7.18 (2H, d, /=7.3 Hz), 5.39 (1H, br s), 4.14 (1H, d, J=7.3 Hz), 2.43-2.68 (2H, m), 1.80-1.88 (2H, m ).

Preparation G 2,4-dioxa-7-phenyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine

7-Phenyl-6,7-dihydro-1/f-cyclopenta[d]pyrimidine-2,4(3//,5/f)-dione (1.241 g, 5.44 mmol) in trichloro The solution in oxyphosphorus (14.93 mL, 163 mmol) was heated in a microwave at 110 °C for 1 hour. Once the ice has melted, the product is extracted with methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting eluting and

[d]pyrimidine (3.132 g, 72%). LC-MS (Μ+Η)+=265.0. 4 NMR (500 MHz, CDC13) δ ppm 7.31-7.37 (2H, m), 7.27 (1H, d, */=7.0 Hz), 7.15 (2H, d, 7=7.9 Hz), 4.44 (1H, t, J=8.2 Hz), 3.09-3.18 (1H, m), 2.97-3.06 (1H, m), 2.73 (1H, ddd, J=9.0, 4.7, 4.6 Hz ), 2·26 (1H, ddd, /=8.5, 7.0, 6 7 Hz). 149653.doc •65· 201107311 Preparation Ga 2-Chloro-N-indenyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]°-biti-4-amine

'NH

To 2,4-dioxa-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation G) (395 mg, 1.49 mmol) in THF (3700 μ! 2 MMeNH 2 in THF (3700 μ [, 7.45 mmol] was added to the solution. The reaction was stirred at room temperature. At the end of the reaction, the solvent was removed and the residue was applied to EtOAc. Medium 5 丨丨 private + qm branch passed to the desired 2-gas-N-mercapto-7-stupyl-6,7-dihydro-5Η-cyclopenta[d] mouth bite __4 η* r Q λ疋4 amine (8〇·8 mg, 0.220 mmol, yield 69.1%). LC-MS (M+H)+=:^n 】, 1 2601 0 H NMR (500 MHz, CDC13) δ ppm 7.07 ( 3H, dd, "/=8 5 s ς u,, 5-5 Hz), 6.96 (2H, t, J=8.7 Hz), 4.72 (1H, br s), 4.23 (1H tr ^ ^ ^=7.2 Hz ), 3.09 (3H, d, /=4.9

Hz), 2.67-2,77 (1H, o &lt; 〇^ λ 2.58-2.67 (2H, m), 2.01-2.11 (1H, m). Preparation Gb 2-gas-iV&quot;,#-dimethyl笨某&amp; i 暴暴-6,7-dihydrocyclopenta[d]pyrimidine-4-amine, hydrazine

149653.doc ,66 - 201107311 2,4-dioxa-7-phenyl-6,7-dihydro-5H-cyclopenta(4)pyrimidine (200 mg '0.754 mmol) and excess diamine (3·77) The solution in MeOH (2 mL) was stirred at room temperature for hr. The solvent was removed in vacuo to give 2- gas dimethyl-7-phenyl-6,7-dihydro-5/^cyclopenta (4)

Mouth-densyl-4-amine (207 mg, 0.756 mmol, yield 1%). [e-MS (M+H)+=274_2 〇 Preparation Gc

2-chloro-fluorenylethyl, methyl-7-phenyl-6,7-dihydrocyclopenta[d]pyrimidin-4-amine

2,4-Dichloro-7-phenyl-6,7-dihydro-5/f-cyclopenta[d]pyrimidine (15 mg, 0.566 mmol) in excess, methylethylamine (〇 486 mL) A solution of 5 66 mmol) in MeOH (2 mL) The solvent was removed in vacuo to give 2-gas-ethyl <-- decyl-7-phenyl_6,7-dihydro_5//_ cyclopenta[d] mouth bite-4-amine (163 mg' 0.566 mmol, yield 1% by weight). LC-MS (M+H)+ = 288. Preparation Gd azetidin *-1-yl)_2·chloro-7_phenyl-6,7-dihydro_5//_cyclopenta[d]pyrimidine 149653.doc •67· 201107311 ◊

2,4-diqi-7-phenyl-6,7-dihydro-5//•cyclopenta[d]pyrimidine (ι 5 mg, 0.566 mmol) and excess azetidine (162 mg) , 2 83 mm 〇i) The solution in methanol (1 mL) was stirred at room temperature for 3 min. The solvent is removed in vacuo to give 4-(azetidinyl), 2, 7-phenyl-6,7-diazepine-dip ring

Pentacene [d] mouth set (162 mg '0.567 mmol, yield 1%). LC-MS (M+H)+ = 286.3. Preparation Ge 2-chlorodidecyl-7-phenyl-6,7-dihydro-5 ugly-cyclopenta[d]pyrimidine-4-amine

To 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine (3 50 mg ' 1.23 6 mmol) and trimethylamine salt DIPEA (0.432 mL, 2.472 mmol) was added to a solution of EtOAc (EtOAc) The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified eluted eluted eluting eluting eluting eluting eluting eluting Cyclopenta[d]pyrimidin-4-amine. LC-MS (Μ+Η)+=281·2. 149653.doc -68- 201107311 Preparation Gf 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]. dense. 4-amine

Change (170 to 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d],

Mg, 0.641 mmol) was added dropwise in a solution of NMP (2 mL), twice per amine (110 mg ' 1.924 mmol). Stir the mixture 3 at room temperature. The product was precipitated by adding 8 mL of water. The solid was filtered off and air-dried to give a 2- gas-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]. 4 (175 mg, 0.612 mmol yield 96%) which was used in the next step without any purification. LC-MS (M+H)+ = 286.1. Preparation Gg 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine_4_amine

To a solution of 2,4-dioxa-7-phenyl-6,7-dihydro-5H-cyclopenta[d], a bite (16 mg, 0-60 mmol) in NMP (2 mL) Add cyclobutylamine (129 mg '1_81 mmol). The mixture was stirred at room temperature for 3 hours. 8 mL of water was added to precipitate the product. The solid was filtered off and dried in air to give crude 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (177 149653.doc-69 · 201107311 mg, 0.5 7 mmol, yield 94%), which was used in the gamma step without any purification. LC-MS (Μ+Η)+=300.1. Preparation of Gh 2-gas-7-phenyl-N-isopropyl-6,7-dihydropyridinium [d]pyrimidin-4-amine

^NH Cl to a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (i72 mg '0.65 mmol) in NMP (2 mL) Propylene-2-amine (115 mg, 1.95 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours. The product was precipitated by adding 8 mL of water. The solid was filtered off, dried in vacuo and purified EtOAc EtOAc EtOAc EtOAc Pentacene [d] is a 4-amine (154 mg, 0.535 mmo yield 82%). NMR (500 MHz, CDC13) δ ppm 7.30 (2 Η, t, 7=7.5 Hz), 7.20-7.25 (1 H, m), 7.15 (1 Η, d, J=1.5 Hz), 7.13 (1 H, s), 4.53 (1 H, d, J = 7.3 Hz), 4.37-4.45 (1 H, m), 4.23-4.28 (1 H, m), 2.58-2.78 (3 H, m), 2.10-2.17 ( 1 H,m),1.27-1.29 (6 H,m) 〇Preparation Gi 2-gas-4-(3-gas valence-1-butyl)-7•phenyl _6,7_2 Hydrogen·5Η_cyclopenta[d]pyrimidine 149653.doc • 70-201107311

Stir 3-Zeta azetidine hydrochloride (217 mg, 1.679 mmol) ' 2,4-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d] at room temperature a mixture of succinimide (150 mg '0.566 mmol) and DIEA (0.395 mL, 2.263 mmol) in N-decyl-2-pyrrolidone (2.0 mL) for 3 h. Water (8 ml) was added to the reaction mixture. The product was precipitated, filtered, washed with water and dried in air. LC-MS (Μ+Η)+=320·0. NMR (500 MHz, gas δ δ ppm 7.21-7.39 (m, 3 Η) 7.14 (d, *7=7.02 Hz, 2 Η) 4.65-4.84 (m, 3 H) 4.34-4.48 (m, 2 H) 4.23 (dd, J=9.\6, 6.41 Hz, 1 H) 3-00 (dd, J=8.85, 5.80 Hz, 1 H) 2.83-2.93 (m, 1 H) 2.54- 2.72 (m,1 H) 2.02-2.20 (m, 1 H). Preparation Gj 2·Alufluoroazetidin-1-yl)-7-phenyl-6,7-diaza-5H-cyclopenta. set

3-Fluoroazetidine The title compound was obtained. The alkane is reacted with the preparation G in the form of the preparation Gi. LC-MS (M+H) ten = 304.1. lH NMR (500 149653.doc 71 201107311 MHZ, gas _d) δ ΡΡΙΪ1 7.19-7.37 (m,3 Η) 7.15 (d Γ να5 «/==7 3? 10.15 ΗΖ, 2 Η) 5.39·5·52 U,i Η) 4.59 (福d, buckle 14 88 ' 5.19,4.88HZ, 2H) 4.3〇_45〇(m,2H) 4 23 (dd ^ 6-26 Hz, 1 Η) 2.96-3.07 (m? 1 H) 2 84.2.96 (m&gt; ι · &gt; 2.70(m,1H)2.05_2.2l(m,iH). 56- Preparation Gk Hydrogen-5H. 2_Gas-4_(3_曱Oxygen Based on heterocyclobutane-1-yl)_7·stupyl-6,7-dicyclopenta[(1] shouting

OMe

The 3-methoxyazetidine and the preparation are prepared as a preparation. LC_MS (M+H)+=316". Inverse

Preparation GI

(2-Chloro-7-phenyl-6,7-dichloro.cyclopenta(4) spurting base oxy-aza snail [3.4] octane

The azetidin-3-ol is reacted with the preparation G in the manner of the preparation (1) 149653.doc -72·201107311 to 1-(2-chloro-7-phenyl-6,7-dihydro-5H-ring Pentans[d]pyrimidin-4-yl)azetidin-3-one. LC-MS (M+H)+ = 300.0. Ethylene glycol (119 is called '2·ι35 mmol), 1-(2-chloro-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]pyran-4-yl)aza a mixture of cyclobutan-3-one (32 mg, 1.068 mmol) and aqueous 4-mercaptobenzenesulfonic acid (20.31 mg, 0.10.7 mmol) in benzene (2965 μΙ&gt;) in a Dean-Stark apparatus (Dean-stark apparatus) was heated under reflux for 24 hours. The resulting mixture was concentrated and purified by preparative HPLC to afford title compound. LC-MS (Μ+Η)+=344·0. NMR (500 MHz, chloroform δ ppm 7.21-7.40 (m, 3 Η) 7.15 (d, *7 = 7.63 Hz, 2 Η) 4·35-4.53 (m, 4 H) 4.23 (dd, /=9.00, 6.26 Hz, 1 H) 4.03 (s, 4 H) 2.96-3.09 (m, 1 H) 2.80-2.96 (m, 1 H) 2.51-2.70 (m, 1 H) 2.03-2.16 (m, 1 H) 〇Preparation G m 2-(2-Ga-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5-oxo-2-aziro[3.4]octane

The 5-oxo-2-aziro[3.4]octane was reacted with the preparation G in the form of the product (1) to give the title compound. LC-MS (M+H)+ = 3421. Preparation Gn 1-(2-chloro-7-phenyl-6,7.dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrole 149653.doc 73·201107311. Ding-3 - Gang

The pyrrolidine-3-one is reacted with the preparation G in the form of the product Gi to give the title compound. LC-MS (M+H)+ = 314.1. Preparation Go 7·(2-Ga-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxo-7-azaspiro[4.4 Decane

Ethylene glycol (46.9 pL '0.841 mmol), 1-(2-gas-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3- A mixture of ketone (intermediate Gn) (132 mg, 0.421 mmol) and aqueous 4-mercaptobenzenesulfonic acid (8.00 mg, 〇042 mmol) in benzene (1169 μ! 在 in a Dean-Stark apparatus) Heating under reflux for 24 hours. The resulting mixture was concentrated by preparative HPLC (column: PHENOMENEX LUNA C18 3 〇χΐ〇 0 mm, solvent A = 10 mM acetic acid 95: 5H20/ACN solution, solvent B = i 〇 mM Acetic acid is described as a 5:95 H2O/ACN solution 'flow rate. 40 ml/min, 30-100, 20 minutes 149653.doc -74·201107311 clocks) to obtain 7-(2-gas-7-phenyl-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxo-7-azaspiro[4.4] brothel (24 mg, 0.067 mmol, yield 15.94%). LC -MS (Μ+Η).=358·1. 4 NMR (500 MHz, M^-d) δ ppm 7.31 (2 Η, t, J=7.63 Hz), 7.20-7.25 (1 H, m), 7.15 (2 H, d, /=7.63 Hz), 4.21 (1 H, dd, J=9.16, 6.10 Hz), 4.01-4.06 (4 H, m), 3.89-3.97 (2 H, m), 3.77-3.84 (2 H, m), 3.26 (1 H, ddd, /=15.03, 8.62, 5.95 Hz), 3.13 (1 H, ddd, /=14.95, 8.85, 5 .80 Hz), 2.53-2.63 (1 H, m), 2.17 (2 H, t, •7=7.17 Hz), 2.03-2.12 (1 H, m). Preparation Gp 2-Chloro-N-(5 -isopropyl-2-mercaptophenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To 2,4-dioxa-7-phenyl-6,7-dihydro-5H-cyclopenta[d]. To a solution of NMP (volume: 7543 μM), 5-isopropyl-4-methylaniline (281 mg ' 1.886 mmol) and DIPEA (329 μΐ, 1.886 mmol) were added. The resulting mixture was brought to i2 ° C and stirred for 2 hours. The mixture was then diluted with EtOAc (EtOAc)EtOAc. Purification by flash chromatography (Chromatography, Thomson 40 g '0-35% EtOAc/hexane) into 149653.doc -75-201107311 to give 2-gas-N-(5-isopropyl-2 -nonylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (81421-078-01) (220 mg, 0.582 mmol, yield 30.9%) ). LC-MS (M+H)+=378.1. 4 NMR (500 MHz, MeOD) δ ppm 7.30-7.41 (3H, m), 7.19-7.26 (3 H, m), 7.16 (2 H, d, J =7.93 Hz), 7.11 (1 H, d, J=7.63 Hz), 4.27 (1 H, t, /=7.63 Hz), 2.91 (1 H, ddd, •7=13.89, 6.87,6.71 Hz), 2.77 -2.86 (1 H,m),2.61-2.76 (2 H, m), 2.24 (3 H, s), 2.03-2.13 (1 H, m), 1.27 (5 H, dd, •/=7.02, 1.53 Hz).

Preparation H 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine

Intermediate H(l) 1-cyclopentenyl-4-fluorobenzene

To a 0.5 M solution of 4-fluorophenylmagnesium bromide in THF (298 mL, 149 mmol) was carefully added cyclopentanone (13.23 mL, 149 mmol). At the end of the addition, the reaction mixture was heated under reflux for 2 hours. Add ice G〇 g) and 6 N aqueous hydrochloric acid. The reaction mixture was extracted with diethyl ether. The organic extract was washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium hydrogencarbonate and water. I49653.doc •76·201107311. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS (M+H)+ = 163.0. *H NMR (500 MHz, CDC13) δ ppm 7.35-7.42 (2H, m), 6.95-7.02 (2H, m), 6.06-6.13 (1H, m), 2.63-2.71 (2H, m), 2.47-2.56 (2H, m), 1.96-2.06 (2H, m). Intermediate H(2) 2-(4-dephenyl)cyclopentanone

A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% nitrogen peroxide (23 mL, 149 mmol) was warmed at 40 ° C for 1 min. The resulting solution was carefully added to 1-cyclopentenyl-4-fluorobenzene (24.1 55 g, 149 mmol) with stirring. The two phase system was initially stirred at room temperature. After a period of time, a self-heating reaction occurred and the temperature rose to about 50 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by the careful addition of saturated sodium bicarbonate solution. Ethyl ether was added and the contents of the separatory funnel were shaken vigorously. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting eluting elution LC-MS (M+H)+ = 177.2. H NMR (500 MHz, CDC13) δ ppm 7.12-7.18 (2H, m), 6.9S-7.04 (2H, m), 3.29 (1H, dd, J=\\.6, 8.5 Hz), 2.42- 149653. Doc -77- 201107311 2.54(2H,m), 2.27(lH,ddd,J=19.1,10_5,8.9Hz),2.12- 2.20 (1H, m), 2.01-2.12 (1H, m), 1.87-1.99 ( 1H, m, /=11.7, 11.7, 8.2, 6.3 Hz) » Intermediate H(3) 7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][i,3] Oxazine·2,4 (3 ugly, 5孖)_

A mixture of 2-(4-indolyl)cyclononanone (18.557 g, 104 mmol) and isocyanomethyl hydrazine (19.77 g, 187 mmol) was taken at 58. (: heating under 1 hour and heating at 130 ° C for 2 hours. After cooling to room temperature, the tarification reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate. The aqueous layer was extracted with EtOAc EtOAc (EtOAc m. 7_Dihydrocyclopenta[e][l,3]oxazine-2,4(3//,5^)c_(13.527 g, 54.7 mmol, yield 52.5%). LC-MS (M+H ) == 248.1. NMR (500 MHz, CDC13) δ ppm 11.80 (1Η, br s), 7.31-7.39 (2H5 m), 7.16-7-22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95 (1H, m) » Intermediate H(4) 7_(4-fluorobenzyl)-6,7-dihydro-1孖-cyclopenta[d]B close bite _2,4(3//,5/f)_ 149653.doc •78- 201107311

7-(4-Fluorophenyl)-6,7-hydrocyclopenta[e][l,3]oxazine-2,4(3,5,5-)-one (13_527 g, 54.7 mmol) The solution in concentrated ammonium hydroxide (15 Torr, 3852 • mm 〇 1) was placed in a high pressure (350 mL) vessel at 1 Torr. The mixture was heated overnight to cool the mixture and cooled to 0 C and filtered. The precipitate is washed successively with water and dried, first air is passed through a filter to dry, and then dried under vacuum reached by the pump to obtain 7-(4-phenylene)-6,7-dihydro-17/ ring guanidine and Mouth bite _ 2,4(3//'5/7)-dione (4.670 g, 18 97 mm 〇1, yield 34 7%). 1^_ MS (M+H)+=247.3 〇 *H NMR (500 MHz, CDC13) δ ppm 11.70-11.81 (2H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H,

m)' 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H ru m), 1.84-1.95 (1H, m). Preparation Η 2,4·diqi-7_(4·fluorophenyl)_6,7-dihydro-5/f_cyclopenta[d]pyrimidine

149653.doc _79· 201107311 bite-2'4(3i/'5T/)-dicopper (1 g' 4.06 mmo丨) in oxygenated phosphorus (1) 8i mL ' 127 mmol) and iV, iV-dimethylaniline ( The solution in 3.94 mL, 31" leg (4) was taken overnight. The reaction mixture was poured carefully to ice. Once the ice was melted, the aqueous layer was extracted with dioxane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The residue was purified by solvent chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc. And [d]pyrimidine (700.0 mg, 2 472 mm()1, yield 60.9%). LC-MS (M+H)+=283.1. iH NMR (500 MHz, CDC13) δ ppm 7.09-7.15 (2H, m), 7.03 (2H, t, J=8.5 Hz), 4.42 (1H, t, 7=8.4 Hz), 3.10 (1H, dd, J=9.2, 4.6 Hz), 3.01 (1H, d, /=8.2 Hz), 2.73 (1H, d, J=8.9 Hz), 2.15-2.27 (1H, m) Preparation Ha 2-Gas-4-(3,3-Fluoroazetidin-1-yl) _7_(4_fluorophenyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidine

Fv F

To 2,4-diqi-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Nongqi #/〇 (521 mg, 1.840 mmol) in MeOH (18.400 mL) DIPEA (0.803 mL ' 4.60 mmol) was added to the solution, followed by 3,3-di 149653, doc -80-201107311 fluazetidine hydrochloride (358 mg, 2 76 mm 〇1). The reaction was stirred at room temperature for 2 hrs then concentrated in vacuo. purified by flash chromatography (EtOAc, EtOAc/hexanes) Fluoroazetidine_ι_yl)·7_(4-fluorophenyl)_6,7-dihydro-5h-cyclopenta[d]pyrimidine (528 mg, 1.554 mmol, yield 84°/.) , which crystallizes upon standing. LC-MS (Μ+Η)+=340·0. 咕NMR (500 MHz, CDC13) δ. ppm 7.05-7.13 (2 H, m), 6.94-7.02 (2 H, m), 4.60 (4 Η, φ td, "/=11.75, 4.27 Hz), 4.18-4.30 (1 H, m), 2.93-3.06 (1 H, m), 2.80-2.95 (1 H, m), 2.56-2.70 (1 H, m), 1.96-2.18 (1 H, m) 〇Preparation Hb (lS,4S)-5-(2-Ga-7-(4-fluorophenyl)-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-5-azabicyclo[2.2.1]heptane

To 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine##//) (200 mg '0.706 mmol) in MeOH (7064) (lS,4S)-2-oxo-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg '0.848 mmol) and DIPEA (271 pL, 1.554 mmol) were added to the solution in pL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo. Purification of the obtained oil by flash chromatography (EtOAc, EtOAc / hexanes) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> ,6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxo-5-azabicyclo[2.2.1]heptane (148 mg, 0.428 mmo yield) 60.6%). LC-MS (Μ+Η)+=346·1. NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2 Η, m), 7.00-7.08 (2 Η, m), 5.11-5.21 (1 Η, m), 4.69-4.74 (1 Η, m), 4.15 -4.26 (1 Η, m), 3.88-3.94 (2 Η, m), 3.68-3.86 (2 Η, m), 3.11-3.21 (1 Η, m), 2.56-2.69 (1 Η, m), 1.92 -2.11 (2 Η, m), 1.24-1.42 (2 Η, m). Preparations Hcl and Hc2 2 -gas-7-(4-fluorophenyl)-4-(2-indolyl 0 to B each 0-dec-1-yl)-6,7-dihydro-5H-cyclopenta[ D]pyrimidine

To 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.706 mmol) To the solution in MeOH (7064 μί) was added 2-mercaptopyrazine (82 μί, 0.848 mmol). The resulting mixture was decanted at room temperature for 2 days. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (EtOAc EtOAcEtOAcEtOAc) 2-Mercaptopyrrole _ 149653.doc -82 · 201107311 1-Base)-6,7-Dihydro-5H-cyclopenta[d]pyrimidine. (孖Ci, diastereomer 1 'excipient oxime' was first eluted) (79.5 mg, 0.240 mmol, yield 33.9%). LC-MS (Μ+Η)+=332·1; 4 NMR (500 MHz, MeOD) Sppm 7.16 (2H, d, J = 5.49 Hz), 7.04 (2H, s), 4.42-4.54 (1 H, m)5 4.09-4.22 (1 Η, m), 3.86-4.00 (1 Η, m), 3.71-3.82 (1 Η, m), 3.24-3.31 (1 Η, m), 3.10-3.22 (1 Η, m), 2.54-2.65 (1 Η, m), 2.05-2.16 (2 Η, m), 1.94-2.05 (2 Η, m), 1.69-φ 1.80 (1 Η,m), 1.27 (3 Η,d , 7=6.10 Hz). (Price 2, diastereomer 2, racemic, second elution) (89.5 mg, 0.270 mmo yield 38%). LC-MS (Μ+Η)+=332·1 ; *H NMR (500 MHz, MeOD) δ ppm 7.14 (2H, d, J=5 Λ9 Hz), 6.99-7.08 (2 H, m), 4.42 -4.54 (1 H, m), 4.13-4.22 (1 H, m), 3.86-4.00 (1 H, m), 3.71-3.83 (1 H, m), 3.25-3.32 (1 H, m), 3.14 -3.25 (1 H, m), 2.52-2.67 (1 H, m), 2.05-2.19 (2 H, m), 1.94-2.05 (2 H, m), 1.68-1.78 (1 H,m), 1.19 -1.32 (3 H,m). The relative stereochemistry of //c/ and % was not determined. Preparation Hd(2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2 ,6-二曱基吗琳

149653.doc -83- 201107311 to 2,4-one gas-7-(4-fluorophenyl)_6,7-dihydro-5Η·cyclopentapyrimidine (袅潆#付) (200 mg, 0.706 mmol) Add cis-2,6-dimethylmorpholine (105, 〇848 mm〇i) to the solution in Me〇H (7〇64 μί). The resulting mixture was stirred overnight at room temperature. An additional 2 equivalents of cis-2,6-dimercaptomorpholine was then added and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (EtOAc, EtOAc, EtOAc) to afford (2,,,,,,,,, 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimercaptomorpholine (223 mg, 0.616 mmol, yield 87%). LC-MS (M+H)+=332.1. 4 NMR (500 MHz,MeOD) δ ppm 7.11-7.24 (2H,m), 6.99-7.09 (2H,m), 4.39-4.51 (2 H, m ), 4.20 (1 H, s), 3.70 (2 H, td, 7=4.12, 2.44 Hz), 3.14-3.25 (1 H, m), 3.03-3.13 (1 H, m), 2.69-2.80 (2 H, m), 2.54-2.68 (1 H, m), 1.95-2.13 (1 H, m), 1.23 (6 H, d, "/= 6.10 Hz) 〇 Preparation He 1-(2-Chlor-7 -(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-indolyl α-bottom-4-ol

To 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Nong 149653.doc -84 - 201107311 潆#//) 400 mg, 1.413 mmol) was added to a solution of MeOH (14.100 mL). Bite-4-ol (163 mg, 1.413 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (c.c., EtOAc/hexane) afforded 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cycloindole[d] Pyrimidine-.4-yl)-4-methylpiperidin-4-ol (374 mg, 1.034 mmol, yield 73.2%). LC-MS (M+H)+=362.0 °1HNMR (500 MHz,MeOD) 5 ppm 7.12-7.21 (2H, m), 7.04 (2H, t, J=8.85 Hz), 4.11-4.30 (3 H , m), 3.48-3.63 (2 H, m), 3.14-3.23 (1 H, m), 3.00-3.12 (1 H, m), 2.54-2.66 (1 H, m), 1.94-2.09 (1 H , m), 1.68 (4 H, t, /=4.12 Hz), 1.28 (3 H, s). Preparations Hfl and Hf2

2-ox-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Combination 2,4-dichloro-7-(4-phenylene)-6,7-dihydro-5H-cyclopenta[d]carcinoma bite (shoulder/##open) (200 mg, 0.706 mmol) with 2-ethylpyrrolidine (84 mg, 0.848 mmol), and purified according to hydrazine' to give two racemic diastereomers 2-chloro-4-(2-ethyl D ratio ° bite - 1 -yl)-7-(4- Iphenyl)· 149653.doc -85- 201107311

6,7-Dihydro-5H-cyclopenta[d]pyrimidine. (///7, diastereomer oxime, elimination of ruthenium first/valley) (?7 mg '0.223 mmol, yield 32%) LC-MS (M+H)+=346. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The relative stereochemistry of T//7 and on, 2 was not determined. Preparation Hg 1-(2-Ga-7-(4-fluorophenyl)_6,7·dihydro-5H_cyclopenta[d]pyrimidin-4-yl) 4-indolepiperidin-4-yl Tert-butyl amide

To 2,4-one gas-7-(4-fluorophenyl)·6,7-dihydro-5H-cyclopenta[d]pyrimidine (Nong##//) (400 mg, 1.413 mmol) in MeOH ( To the solution in 14.1 mL) was added 3-mercaptopiperidine-4-ylamino decanoic acid tert-butyl ester (3 〇 3 mg, 1.413 mmol). The resulting mixture was stirred at room temperature for 7 days. At this point, the vacuum vortexed the reaction mixture. Purification by flash chromatography (cerium oxide, Et 〇Ac / hexane) gave a yellow bubble (2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Pentans[d]pyrimidin-4-yl)-4-indolylpiperidine-4-ylaminofurfuric acid dibutyl vinegar (159 mg, 0.345 mmol, yield 24.41%). LC-MS (M+H)+=461.2 ° !H NMR (500 MHz, MeOD) δ ppm 7.12-7.22 (2 H, m), 6.98-7.09 (2 H, m), 4.19 (3 H, d, /=2.14 Hz), 149653.doc -86 · 201107311 3.38-3.56 (2 H, m), 3.13-3.25 (1 Η, m), 3.02-3.13 (1 Η, m), 2.53- 2.67 (1 Η, m), 2.11-2.24 (2 Η, m)j ι.96-2.08 (1 H, m), 1.53- 1.65 (2 H, m), 1.47 (9 H, s), 1.37 (3 H, s) . Preparation Hh 2-gas-7-(4-fluorophenyl)-N-mercapto-6,7-digas·5Η_cyclopenta[d]pyrimidine-

4-amine \|MH

Combination of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Nongqi #//) (500 mg, 1.766 mmol) with hydrazine Amine hydrochloride (179 mg, 2.65 mmol), and purified according to Agrobacterium to give 2-chloro-7-(4-fluorophenyl)-indole-indoleyl-6,7-dihydro-5Η- Cyclopenta[d]pyrimidin-4-amine (344 mg, 1.239 mmol, yield 70.1%). LC-MS (Μ+Η)+=278·0. *H NMR (500 MHz, CDC13) δ ppm 7.03-7.12 (2 Η, m), 6.91-7.03 (2 Η, m), 4.53-4.79 (1 Η, m), 4.19-4.29 (1 Η, m) , 3.09 (3 Η, d, 7=4.88 Hz), 2.56-2.80 (3 H, m), 2.00-2.15 (1 Η, m). Preparation m 1-(2-Chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(tri-IImethyl) 》比 Each bite-3-ol 149653.doc -87- 201107311

Combination of 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Nong Guangyou //) (286 mg, 1.010 mmol) with 3 -(Trifluoromethyl) ° than the mouth. D--3-ol (I57 mg '1.010 mmol), and purified according to the cultivar 6 to give 1-(2-chloro-7-(4-lacylphenyl)-6,7-dihydro-5H- Cyclopenta[d]1^ ate-4-yl)-3-(trifluoromethyl). Bilobidine-3-ol (yield 62%). LC-MS (M+H)+= 402.0 ° Preparation Hj 1-(2- gas- 7-(4-fluorophenyl)-6,7-dichloro-5H-cyclopenta[d]°^^ -4-yl)-N,N-dimethylpyrrole-3-amine

Combination of 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (裘潫参//) (1〇〇11^, 0.353 111111 〇1) and ]^,;^-dimethylpyrrolidine-3-amine (44.3 μιη, 0.353 mmol), and purified according to 裘潆//6 to give 1-(2- gas-7-(4) -fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)- 149653.doc •88· 201107311 N,N-dimethylpyrrolidine-3-amine (109 Mg, yield 86%). LC-MS (M+H)+ = 361.2. Preparation Hk 2_Chloro-7-(4-fluorophenyl)-4-(4-indolylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

F combines 2,4 -diqi- 7-(4-d-phenyl)-6,7-dihydro-5H-cyclopenta[d]. Ηη定(农##//)(100 mg, 0.353 mmol) and 1-曱 base. Qin (39.2 pL, 0·353 mmol), and purified according to Nongqian #///? to give 2-qi-7-(4-fluorophenyl)-4-(4-methylpyrazine-1- 6,6-Dihydro-5H-cyclopenta[d](b) (109 mg, 0.314 mmol, yield 89%). LC-MS (Μ+Η)+= 347.2.

Preparation m 4-(2-Chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinyl)piperazine-1-carboxylic acid tert-butyl

149653.doc -89- 201107311 Combination 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-511-cyclopenta[&lt;1]pyrimidine (虞/菜#开) (100 mg, 0.353 mmol) and 1-butylpyrazinecarboxylic acid tert-butyl ester (65.8 mg, 0.353 mmol), and purified according to 潆漱//6 to give 4-(2- gas-7-(4-fluoro) Phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-decanoic acid tert-butyl ester (116.9 mg, yield 76%). LC-MS (M+H)+ = 433.3. Preparation Hm 1-(2-Ga-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl (fluorenyl) Aminobutyl citrate

Combination 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d] mouth bite (attacked 7 7/) (100 mg '0_353 mmol) and 3-(N-Tertioxybutyryl_n_methylamino)"Bilo bite (69_4 μ!&gt;, 0.353 mmol)' and purified according to the start of the farm to obtain 1-(2-chloro-7) -(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(indenyl)amine decanoic acid tert-butyl vinegar (148 Mg, yield 94%). LC-MS (M+H)+ = 447.2. Preparation Ηη 1-(2-Ga-7-(4-fluorophenyl)-6,7·dihydro-511-cyclopenta[(1]Bite _4_美) M9653.doc •90- 201107311 Azetidine, azetidin-3-yl(indenyl)carbamate

• Combination 2,4-digas _7_(4_fluorophenyl)_6,7·dihydro-5H_cyclopenta[d]pyrimidine (agricultural #//) (100 mg, 0.353 mmol) with an amine group 3-azetidinyl-1,1-dimethylethyl formate (82 mg, 0.441 mmol), and purified according to agromic acid to give 1-(2_chloro_7_(4-fluorophenyl) )_6,7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)aminocarbamic acid tert-butyl ester (147 mg ' yield 96% ). LC-MS (Μ+Η)+=377·1. Preparation Ho M2-gas-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-# Ν, Ν-dimethyl nitrogen heterocycle Butyl-3-amine

Combination 2,4_diqi-7-(4-dephenyl)-6,7-dihydro-5Η-cyclopenta[(1] 〇定定(农菜#//)(100 mg, 0.35 3 Ment) with ν, Ν-dimethylazetidine 149653.doc • 91- 201107311 3-amine dihydrochloride (122 mg, 0.706 mmol), and purified according to 涝#/^ to get 1-( 2-Chloro-7-(4-fluorophenyl)·6,7-dihydro·5H_cyclopenta[d]pyrimidin-4-yl)-N,N-dimethylazetidine_3_ Amine (quantitative) LC_MS (M+H)+ = 347.2. Preparations Hpl and Hp2 2- gas-7-(4-fluorophenyl)-4-((S)-3-fluoro)pyrrolidyl) _6 7_Dihydro-5H-cyclopenta[d]pyrimidine

To 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidine (preparation H) (135 mg, 0.477 mmol) in MeOH (4768 DIPEA (208 μιη, 1.192 mmol) was added to the solution in μί). Then (s)-3-fluoropyrrolidine (46.7 mg, 0.524 mmol) was added. The mixture was stirred at ambient temperature for 2 hours. The solvent was removed and the residue was applied to a silica gel and eluted with a gradient of Et EtOAc/Hex to give two diastereomers (7) and s. ^^^ MS (Μ+Η)+=336·2. 'H NMR (500 MHz, CDC13) δ ppm 7.06-7.13 (2 Η, m), 6.93-7.00 (2 Η, m), 5.32 (1 Η, td, 52.57, 3.17 Hz), 4.17 (1 H, dd , /=9.16, 5.49 Hz), 4.06-4.14 (1 H, m), 3.98-4.06 (1 H, m), 3.76-3.90 (2 H, m), 3.25 (1 H, ddd, /=15.1 1 , 8.55, 6.26 Hz), 3.08-3.16 (1 H, m), 2.51-2.60 149653.doc 92- 201107311 (1 H, m, 7=13.20, 9.12, 9.12, 6.41 Hz), 2.32-2.42 (1 H , m), 2.00-2.17 (2 H, m). Hp2: LC-MS (Μ+Η)+=336·2. 'H NMR (500 MHz, CDC13) δ ppm 7.06-7.14 (2 H, m), 6.94-7.02 (2 H, m), 5.25-5.40 (1 H, m), 3.99-4.24 (3 H, m) , 3.75-3.92 (2 H, m), 3.19-3.28 (1 H, m), 3.10-3.19 (1 H, m), 2.57 (1 H, dddd, /=13.24, 8.74, 8.55, 4.58 Hz), 2.31-2.43 (1 H, m), I. 94-2.17 (2 H, m).

Preparation Hq 2-gas-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d] Pyrimidine

2,4-Gas-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) and (R)_3_Fluor D The reaction removal/mixtures were taken as described in the preparations and My and the residue was applied to the oxime and passed to the combined two diastereomers (Hq) with a gradient of Et 〇Ac/Hex.

Hal: LC-MS (M+H)+=336.〇. Preparation Hr gas 4 (4,4-one gas „定小基)·7_(4_fluorophenyl)-6,7_二气·5η_cyclopenta[d]pyrimidine 149653.doc -93- 201107311

To 2,4-dioxa-7-(4-fluorophenyl)-6,7-di-argon-5H-cyclopenta[d]pyrimidine (preparation H) (90 mg '0.318 mmol) in MeOH (3179 ΐ) In the solution in ^)

Add 4,4- a chaotic bottom bit (11 5 mg, 〇·95 mmol). Mix the reaction at room temperature. When the reaction is complete, the solvent is removed and the residue is applied to the silicone. Dissolve in EtOAc/Hex to give the desired 2-chloro-4-[(4,4-difluoropiperidinyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[ d] Pyrimidine (80.8 mg, 0.220 mmol, yield 69.1%). LC-MS (M+H)+ = 368.0. Preparation Hs 2_ gas-4-(4-fluoro-5,6-dihydro.pyridin-1(2H)-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H- Cyclopenta[d]pyrimidine

2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) with 4-fluoro-i, 2,3, 6-tetrahydropyridine reacts as described in the preparation of He's to 2-gas-4-(4-fluoro-5,6-dihydropyridine-1(2H)-yl)-7-(4- Fluorobenzene 149653.doc -94·201107311 base)-6,7-dihydro-:5H-cyclopenta[d]pyrimidine (preparation Hs). Preparation m 2-gas-7-(4-fluorophenyl)-4-(3-(trifluoromethyl) n-pyridyl-i-yl)-6,7-dihydro-5H-cyclopenta[ d]pyrimidine 4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

0 /CF3

2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Preparation H) is reacted with 3-trifluoromethylpyrrolidin as described in 涝# to give 2_gas_7_(4-fluorophenyl)- in the form of a mixture of four diastereomers. 4-(3-(Trifluorodecylpyrrolidine-bu)), 'Dihydro-5H cyclopenta[d]pyrimidine 4-fluorophenyl)-6,7-dihydro-5H-cyclopenta [d] Pyrimidine (preparation Ht). LC-MS (M+H)+=386.1 ° lR NMR (500 MHz, CDC13) δ ppm 7.05-7.11 (2 Η, m), 6.96 (2 Η, t, /=8.70 Hz), 4.14-4.20 (1 H, m), 3.89-4.02 (2 H, m), 3.75-3.86 (2 H, m), 3.17-3.28 (1 H, m), 3.06-3.16 (1 H, m), 2.99 (1 H, Dq, 7-15.95, 8.01

Hz), 2.50-2.61 (1 H, m), 2.13-2.30 (2 H, m), 1.95-2.06 (1 H, m). Preparation Hu 2-Gas-N-(3-ethoxypropyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine 149653. Doc -95- 201107311 cr,N,^ Q.

F 2,4·diqi-7-(4-fluorophenyl)-6,7-dihydro-5H·cyclopenta[d]pyrimidine (preparation H) ” 3 -ethoxypropane-1 _ The amine reacts as described in the preparation ηγ to give J chloro N(3-ethoxypropyl)_7_(4-fluorophenyl)_6,7-dihydro·5H_cyclopenta[d]. 4-Amine (Preparation Hu). LC_ms (Μ+Η)+=350·1. Preparation Ην 3-(2-Ga-7-(4-fluorophenyl)_6,7-Dihydro_5Η_ Cyclopenta[d]pyrimidine _4_yl

Amino)propan-1-ol HN^^^OH

Preparation of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) with 3-hydroxypropan-1-amine The reaction is carried out as described in the product Hr to give 3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propyl- 1-Alcohol (Preparation Hv). LC-MS (M+H)+ = 3221. NMR (500 MHz, CDC13) δ ppm 7.08 (2H, dd, J=8.55, 5.49 Hz), 6.97 (2 H,t,J=8.70 Hz), 5.18 (1 H,br. s.),4.22- 4.27 (1 h, m), 3.66-3.75 (4 H, m), 3.18 (1 H, br. s.) 5 2.60-2.77 (3 H, m), 2.02-2.12 (1 H, m), 1.78 -1.86 (2 H,m). Preparation Hyo 149653.doc •96· 201107311 2_Chloro-N-(l-cyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-amine

Making 2'4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) with 1-cyclopropyl-2-methoxy Ethylethylamine reacts as described in the preparation Ηγ to give 2_gas_Ν·(1_ propylpropyl 2 methoxyethyl)-7-(4) in the form of a mixture of four diastereomers. -fluorophenyl)-6,7-dihydro-5 oxime-cyclopenta[d]pyridin-4-amine (preparation Hw). LC-MS (Μ+Η)+=362·1. Preparation Ux 2-gas-7-(4-fluorophenyldifluorenyl-6,7-dihydro-5孖·cyclopenta[d]pyrimidine

Pyridine-4-amine, N〆

2,4-Dichloro-7-(4-fluorophenyl)-6,7-dihydro-5//-cyclopenta[d] mouth bite (260 mg, 0.918 mmol) and at a temperature A solution of excess diamine (4 59 mL, 9.18 mm 〇l) in decyl alcohol (2 mL) was taken for 30 min. The solvent was removed in vacuo to give crude 2-chloro-7-(4-fluorophenyl X, dimethyl-6,7-dihydro-5 oxime 149653.doc-97-201107311 penta[d]pyrimidine-4 -amine (268 mg, 0.919 mmol, yield 100%). LC-MS (M+H)+==292.3. Preparations Hy 2 - gas-7-(4-phenylphenyltrimethyl-6,7 -dihydro-5//_cyclopenta[d]pyrimidin-4-amine

To 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine (35 0 mg ' 1.236 mmol) and triterpene salt DIPEA (0.432 mL, 2.472 mmol) was added to a solution of EtOAc (EtOAc, EtOAc. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified eluted eluted eluted elut elut - cyclopenta[d]pyrimidine (350 mg '1_236 mmol). LC-MS (Μ+Η)+=281·2. Preparation Hz 2-gas-7-(4-fluorophenyl)-:^-((尺)-1-曱oxybutan-2-yl)-6,.7-dihydro-

M9653.doc -98- 201107311 to 2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) (100 mg, (R)-l-decyloxybutan-2-amine hydrochloride (197 mg, 1.413 mmol) and DIEA (493, 2.83 mmol) were added to a mixture of THF (1766 kL). The mixture was heated at 60 ° C for 3 days. The crude product was purified by preparative HPLC to give 2-[rho]-7-(4-fluorophenyl)-indole ((R)-l-methoxybutan-2-yl)-6,7-dihydro- 5Η-cyclopenta[d]pyrimidin-4-amine (preparation Hz) (78 mg, 0.223 mmol, yield 63.1%). LC-MS φ (M+H)+=350.4 ° !H NMR (500 MHz, CDC13) δ ppm 7.12 (dd, J=8.24, 5.49 Hz, 2 H) 6.87-7.05 (m, 2 H) 4.86 (d , J=7.63 Hz, 1 H) 4.35 (d, J=3.05 Hz, 1 H) 4.18-4.30 (m, 1 H) 3.47-3.60 (m, 2 H) 3.40 (d, J = 6.71 Hz, 3 H 2.62-2.82 (m, 3 H) 2.03-2.15 (m, 1 H) 1.58-1.78 (m, 2 H) 0.89-1.07 (m, 3 H). Preparation Haa 2-chloro-N-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-φ cyclopenta[d]pyrimidine- 4-amine

To 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) (100 mg, 0.353 mmol) in THF (1766) (R)-l-cyclopropylethylamine hydrochloride (172 mg, 1.413 mmol) and 149653.doc -99-201107311 DIEA (493 pL, 2_83 mmol) were added to the solution. The mixture was stirred at 60 ° C for 5 days. The crude product was purified by preparative HPLC to give 2- gas-N-((R)-1-cyclopropylethyl)-7-(4-phenylphenyl)-6,7-dihydro-5H- ring. Pentylene [d] mouth bite 4-amine (preparation Haa) (74 mg, 0.223 mmol, yield 63.1%). LC-MS (M+H)+= 332.3. 4 NMR (500 MHz, CDC13) δ ppm 7.06-7.18 (m, 2 H) 7.00 (td, 1 = 8.70, 1.53 Hz, 2 H) 4.65 (d, J =5.80 Hz, 1 H) 4.26 (t, J=7.17 Hz, 1 H) 3.63-3.79 (m, 1 H) 2.62-2.82 (m, 3 H) 2.04-2.16 (m, 1 H) 1.26-1.40 ( m, 3 H) 0.94 (qd, J = 8.24, 3.36 Hz, 1 H) 0.42-0.62 (m, 3 H) 0.24-0.40 (m, 1 H). Preparation Hab 2 -Chloro-N-((S)-1-cyclopropylethyl)-7-(4,fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. 4-amine

2,4-dioxa-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation H) with (S)-l-cyclopropyl The amine hydrochloride reacts as described in the preparation Haa to give 2-chloro-N-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-di Hydrogen·5Η-cyclopenta[d]pyrimidin-4 amine (preparation Hab). </ RTI> <RTIgt; 1 H) 4.26 (t, J=7.32 Hz, 1 H) 3.61-3.79 (m, 1 H) 2.62-2.82 (m, 3 149653.doc •100- 201107311 ) 2*16 (m, 1 H) 1.25- 1.39 (m, 3 H) 0.84-1.00 (m, 1 H) 0.42-0.62 (m, 3 H) 〇29_〇4〇 (called ih). Preparation Hac (gas 7 (4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylazetidin-3 carbonitrile

The title compound is obtained by reacting 3-nitro-3-methylazetidine with the preparation oxime in the form of the product Gi. LC-MS (M+H)+ = 343.0. Towel NMR (5 〇〇 MHz, gas δ δ ppm 6.96-7.13 (m, 5 H) 4.73 (d, «7=6.71 Hz, 1 Η) 4.35 (d, 7=7 32 Hz, 2 Η) 4.33 (br · s·,1 Η) 4.27 (dd, 7=9.00, 2.9〇Hz, 1 H) 2.99-3.09 (m, 1 H) 2.85- 2.99 (m, 1 H) 2.64-2.78 (m,i H) 2.11 (dd, J=13.89, 7.48

Hz, 1 H) 1.76-1.91 (m, 3 H) oxime preparation Had 2_gas-4-(3-ethoxyazetidinyl-fluorenyl); 7_(4-fluorophenyl; ·6,7-Dihydro-5Η-cyclopenta[d]pyrimidine 149653.doc -101 - 201107311 OEt

F The 3-ethoxyazetidine and the preparation h were prepared as the title compound. LC-MS (Μ+Η)+=348·〇. NMr (500 MHz, gas δ ppm 7 〇3 7 12 (called 2 h) 6 μ ? 〇ι (eg 2 Η) 4.51 (br. s.5 2 H) 4.36-4.48 (m, 1 H) 4.13- 4.32 (m H) 3.50 (qd,j=6 97, 3 2〇Hz, 2 H) 2 97 3 i〇^ 2』23· 2-96 (m, 1 H) 2.51-2.70 (m, 1 H) 1.93-2.11 (m, ! H) ' 1.35 (m,3 H). 6' Preparation Hae W2-gas-7-(4-fluorophenyl)_6,7-dihydro·5H-cyclopenta(4) 3-mercaptoazetidin-3-ol

CI

The title compound was obtained by reacting 3-methylazetidin-3-ol with the preparation of the preparation. LC_MS (M+H)+=334 〇. 4(10) feet (500 MHz, chloroform...δ ppm 7 〇4 713 (m, 2 h) 7 勒 R 149653.doc -102· 201107311 7=8.55 Hz, 2 Η) 4.41 (d, *7=6.71 Hz, 2 Η ) 4.39 (br. s.,3 Η) 3.05-3.17 (m,1 h) 2.90-3.04 (m,1 H) 2.73 (ddd,^9.〇8, 4.88' 4.65 Hz, 1 H) 2.03-2.19 (m, 1 H) 1.65 (s, 3 H). Preparation Haf 2 mouse 7 (4 -murine base)-·4-(3_methoxy_3_indolyl azepanidine _i_yl)-6,7-dihydro-511-cyclopenta [£1]pyrimidine OMe

C|AN is reacted in the same manner as the preparation Gi by 3-methoxyl_3-methicone μ^, c^ oxetium butane to obtain the title ~m. LC-MS (M+H)+=348. Preparation 1 2,4-Dichloro-8·stupyl _ 5 A 'murine-511-8 bottom D South and [4,3-d] ° dense. set

CI octa N intermediate 1 (1) 3-iodo-4,4-dimethoxytetrahydro-2H-pyran 0.

149653.doc 0 • 103 - 201107311 Slowly add iodine (49.2 mL, 200 mm 〇i) to tetraterpene-4H-0 thiopyran-4-one (1 8.52 mL, 200 mmol) over 10 min at 〇C. A mixture of trimethyl decanoate (100 mL, 914 mmol). At the end of the addition, the reaction mixture was stirred at 〇〇c for 30 minutes, then allowed to reach room temperature and stirred until TLC indicated that all starting material had been consumed (about 1 hour). The reaction was then cooled to o ° c and was quenched by the slow addition of saturated aqueous sodium thiosulfate (3 mL). The resulting mixture was extracted with EtOAc (3 X 75 mL). The combined organic layers were washed with brine (1 mL) dried over EtOAc EtOAc. Purification by flash chromatography (EtOAc, EtOAc / EtOAc) Yield 81%). NMR (500 MHz, CDC13) δ ppm 4.25 (1 Η} q, /=2.44 Hz), 3.93-4.01 (1 H, m), 3.84-3.93 (2 H, m), 3.57 (1 H, td, 7 =11.75, 2.44 Hz), 3.19-3.30 (6 H, m), 2.34 (1 H, ddd, 7=14.34, 12.21, 4.88 Hz), 1.80 (1 H, dq, 7=14.34, 2.44 Hz). Intermediate 1(2) 3·Phenyl II - 2Η·^Π南·4(3Η) - Tongtong

To phenyl lysine (16.81 g, 138 mmol), trans-2-aminocyclohexanol hydrochloride (1.393 g, 9.19 mmol) and nickel hexahydrate hexahydrate (11) over 10 min at 〇 ° C ( 1.092 g, 4.59 mmol) bis(trimethylsulfonylalkyl)amine sodium (1_〇M THF solution) was added dropwise to a mixture of THF (92 mL) (184 149653.doc •104·201107311 mL) , 184 mmol). When the addition was complete, the reaction mixture was bubbled with n2 for 15 knives. Next, 2-propanol (375 mL) was added to the reaction mixture under 〇 C (previously &amp; bubbling). The mixture was brought to room temperature, at which time 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate 1 (1)) (25 g, 92 mmol) was added dropwise over 5 min. . The reaction mixture was then allowed to reach 6 Torr and stirred overnight. The reaction mixture was then cooled to and quenched by carefully adding aqueous hydrazine N aqueous acid until acid. The mixture was extracted with Et 〇Ac (3 x 15 〇 mL). The combined organic extracts were washed with EtOAc (EtOAc EtOAc (EtOAc) Dihydro-2H-piperidin-4(3H)-one (8.37 g, 47.5 mmo yield 51.7.). H NMR (500 MHz, CDC13) δ ppm 7.32-7.39 (2 Η, m), 7.26 -7.31 (1 Η, m), 7.21-7.26 (2 Η, m), 4.17-4.31 (2 Η, m), 3.91- 4.05 (2 Η, m), 3.78 (1 Η, dd, "/=8.55 , 6.10 Ηζ), 2.61-2.74 (1 Η, m), 2.51-2.61 (1 Η, m) 〇φ Intermediate 1(3) 8-phenyl-7,8-dihydropyrano[3,4_e ][1,3]oxazine-2,4(3Η,5Η)dione

In the sealed tube, 3-phenyldihydroindolyl-pyrano-yl)-one (intermediate 1(2)) (3 g, 17.02 mm〇l) and isocyanoindole (1〇48 g) The mixture of 29 8 mmol) was heated to 58 t and stirred for a few hours. The mixture was then brought to 149653.doc 201107311 to 130 ° C and stirred for a further 2 hours. During this time the reactants turned black. After cooling to room temperature, the tar was dissolved in EtOAc (100 mL). The solution was washed with aq. EtOAc (EtOAc) Purification by flash chromatography (EtOAc, EtOAc / hexanes) ° ° ° Qin-2,4 (311,511)-dione (2.58, 10.52 mmol, yield 61.8%). LC-MS (M+H)+=246.0. 4 NMR (500 MHz, MeOD) δ ppm 7.34-7.41 (4H, m), 7.29- 7.34 (1 H, m), 4.42-4.63 (2 H, m ), 4.08-4.15 (1 H, m), 3.94 (1 H, dd, /=11.44, 4.12 Hz), 3.85 (1 H, ddd, J=4.20, 2.44, 2.21 Hz). Intermediate 1(4) 8 - Benyl-7,8-dihydro- ΙΗ-β-deoxy[4,3-d]^^_2,4(3H,5H)-:_

8-Phenyl-7,8-dihydropyrano[3 4_e][13]oxazine-2,4(3H,5H)-diindole (intermediate 1(3)) in a sealed tube (2.58 g, 1〇52 _〇ι) The solution in ammonium oxynitride (28.7 mL, 736 mm 〇l) was heated to 8 〇t: and stirred overnight. The reaction mixture was then concentrated to dry to give &lt;RTI ID=0.0&gt;&gt;&gt; Fixed · 2, 4 (3H, 5H) _ two identical. The crude material is used as it is. LC-MS (Μ+Η)+=245·2. Preparation 1 149653.doc •106· 201107311 2,4-chloro-8-phenyl-7,8-dihydro-511-spoken and [4,3-&lt;1]

8-Phenyl-7,8-dihydro-1H-piperazo[4,3-d]pyrimidine-2,4(3H,5H)-dione (Intermediate 1(4)) in a sealed tube A mixture of (2569 mg, 10.52 mmol) and POCl3 (29.400 mL '315 mmol) was heated to 100 t under microwave irradiation: '1 hour. The resulting mixture was poured onto ice. When all the ice had melted, the mixture was extracted with EtOAc (3 X 15 mL). The combined organic extracts were washed with brine (2 mL) dried over EtOAc EtOAc. Purification by flash chromatography (cerium oxide, EtO Ac / hexane) afforded 2,4-dichloro-8-phenyl-7,8-di- ar- 5H-nitrix [4,3-d ] shouted (194 mg, 0.690 mmol, yield 6.56%). LC-MS (Μ+Η)+=281·1. ^ NMR (500 MHz, MeOD) δ ppm 7.30-7.37 (2 H, m), 7.25-7.30 (1 H, m), 7.18-7.25 (2 H, m), 4.90-5.00 (i H, m), 4.75- 4·84 (1 H, m), 4.16-4.26 (2 H, m), 4.02-4.15 (1 H, m). Preparation la 2-gas-N-methyl-8-phenyl-7,8-dihydro-5 H-0 benzo[4,3_d] mouth bite 4-amine

-107- 149653.doc - 201107311 To 2,4-dioxa-8-phenyl-7,8-dihydro-5Η-β-dea[4,3-d], a bite (preparation 1) (194 Methylamine hydrochloride (69.9 mg, 1.035 mmol) and N,N-diisopropylethylamine (3 01.μί ' 1.725 mmol) were added to a solution of MeOH (EtOAc). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (2M, EtOAc / hexanes) Tep-4-amine (126 mg, 0.457 mmol, yield 66.2%). LC-MS (M+H)+=276.0. 4 NMR (500 MHz, CDC13) δ ppm 7.28 (2H, t, J=7.32 Hz), 7.20-7.25 (1 H, m), 7.14-7.20 (2 H, m), 4.47-4.62 (2 H, m), 4.47 (1 H, s), 4.00- 4.11 (2 H, m), 3.95 (1 H, d, /=3.36 Hz), 3.08 (3 H , d, • 7=4.88 Hz). Preparation ib 2-gas-7\/', _/^-dimethyl-8-phenyl-7,8-dihydro-5//-» bottom &lt;1 Nanhe [4,3_(^] 11 dense

Stir 2,4-dichloro-8-phenyl-7,8-dihydro-5/i-pyrano[4,3-compound (135 mg, 0.480 mmol) and excess dimethylamine at room temperature (216 mg, 4.80

Methyl acetate in MeOH (2 mL) for 1.5 h. The solvent was removed in vacuo to give 2-chlorodimethyl-8-phenyl-7,8-dihydro-57/-pyrano[4,3-d]pyrimidine-4-amine (139 mg &gt; 0.480 mmol, yield 100%). LC-MS 149653.doc -108- 201107311 (Μ+Η)+=290·3 〇Preparation lc 2-gas-#-ethyl-#-methyl-8-phenyl-7,8-dihydro- 5//-piperido[4,34]pyrimidin-4-amine

2,4-Dichloro-8-phenyl-7,8-dihydro-5//-π bottom β-[4,3-d] mouth bite (135 mg, 0.480 mmol) at room temperature A solution of excess hydrazine/methylethylamine (284 mg, 4.80 mmol) in MeOH (2 mL) The solvent was removed in vacuo to give 2·chloro-iV-ethyl-iV-mercapto-8-phenyl·7,8-dihydrodeoxy[4,3-&lt;^]. 4-amine (146 mg, 0.481 mmol, yield 1%). MS (M+H)+ = 304.2. Preparation J: 2,4-Dichloro-8-(4-fluorophenyl)-7,8-dihydro-511-piperazino[4,3-(1]pyrimidine

Intermediate J(l): 3-bromodihydro-2H-piperidin-4(3H)-one

149653.doc •109- 201107311 Add pyrrolidine to a cooled solution of dihydro-2H-pyran-4-(3Η) ketone (i〇〇g, 99.8 mm〇i) in THF over 10 min at 〇C A solution of ketone hydrogen tribromide (49.54 g '99.8 mm 〇1) in THF. The reaction mixture was allowed to reach room temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (300 ml). The organic solution was washed with a saturated aqueous solution of NaHCI (3 mL), water (100 mL×2), and brine (50 mL), dried over anhydrous NaCI, and evaporated under reduced pressure to give an oily liquid. Hydrogen-2H-piperan-4(3H)-one (12.0 g, 67%). The crude compound was used in the next step without further purification. 1H NMR (4〇0 MHz, DMS〇_^): § ppm 4.89-4.87 (1Η,m) 4.28-4.27 (1Η, m) 4.25-4.4.24 (1Η, m) 3·85·3.74 (2H, m) 2.71-2.66 (2H, m). ' Intermediate J(2): 3-(4- gas group)-hydrogen-2Η-α-endan-4(3H)-one

To a solution of the intermediate J(l) (12.0 g' 66.9 mmol) in EtOAc, EtOAc (EtOAc m. . The reaction mixture was stirred at room temperature for 4 minutes. The reaction mixture was quenched with 1.5 N aqueous hydrochloric acid (80 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100x2). The combined organic layers were washed with EtOAc (EtOAc m. The crude compound was dissolved in benzene and a solution of 4-fluorophenyl magnesium bromide in diethyl ether (9 7 149653.doc • 110-201107311 g ' 24.5 mL ' 49.0 mmol) was added. The reaction mixture was heated under reflux for 30 minutes. The reaction mixture was quenched with aq. EtOAc (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 EtOAc). The combined organic layers were washed with EtOAc (EtOAc)EtOAc. The crude compound was purified by column chromatography (tantalum '230-400 mesh) using 5% ethyl acetate petroleum ether as mobile phase to give 3-(4-fluoro-phenyl)dihydro as an oily liquid. -2H-piperidin-4(3H)-one (3.0 g, 36%). LC-MS (M+H)+=195.2. 4 NMR (400 MHz, EMI - 〇: δ ppm 7.7.21-7.18 (2H, m), 7.06-7.01 (2H, m), 4.28-4.21 ( 2H, m), 3.99-3.91 (2H, m), 3.79-3.76 (1H, m), 2.72-2.67 (1H, m), 2.64-2.55 (1H, m). Intermediate J(3) 8-( 4-fluorophenyl)-7,8-dihydropyrano[3,4&lt;][1,3]oxazine-2,4(3H,5H)-dione

F A solution of the intermediate J(2) (1.5 g, 7.72 mmol) and N-gas episoisocyanate (0.97 g, 9.2 mmol) was heated at 58 ° C under a nitrogen atmosphere. The reaction temperature was then increased to 130 ° C and maintained for 2 hours. The reaction mass was diluted with ethyl acetate (50 mL). Saturated NaHC03 (25 mL), brine solution 149653.doc -111· 201107311

The obtained organic solution was washed with (25 mL), dried over anhydrous NaHEtOAc, and evaporated. The crude compound was purified by column chromatography (EtOAc, EtOAc (EtOAc): EtOAc (EtOAc) 8 dihydropyrano[3,4-eni,3]^,-2,4(3H,5H)c_(〇.8g, 38%) &lt;&gt;&gt;LC_MS (MH)+ = 262.0. NMR (400 MHz, DMSO-Liu δ ppm 11.97 (1H, s), 7.43-7.39 (2H, m), 7.21-7.16 (2H, m), 4.48- 4.32 (2H, m), 4.05 (2H, m) , 3.77 (1H, m). Intermediate J(4) 8-(4-fluorophenyl)-7,8-dihydro-1H-pyrano[4,3_d]pyrimidine _ 2,4(3H,5H )-dione

A solution of the intermediate J(3) (0.8 g, 3.0 mmol) in aqueous ammonia (50 mL) was evaporated. Excess ammonia was removed under reduced pressure and the aqueous solution was extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (25 mL) dried over anhydrous Nat. -d]pyrimidine_2,4(3H,5H)-dione (〇.4 g, 50%). The crude compound was used in the next step without further purification. MS (M+H)+=263.4 NMR (400 MHz, DMSO-^): δ ppm 11.16 (1H, s), 10.79 (1H, s), 7.33-7.29 (2H,m), 7.19-7.15 149653.doc •112- 201107311 (2H,m),4.43 (1H,m), 4.25 (1H,m),3.90 (1H,m),3.75 3.68 (2H , m).

Preparation J 2,4-dioxa- 8-(4-fluorophenyl)-7,8-dihydro-5H-e benzo[4,3_d] spray

F

The intermediate J(4) (0.7 g, 2.6 mmol) and the catalytic amount of dmf were added to POCl;j (20 vol); the broth was heated under reflux for 18 hours. Excess POCI3 was evaporated under reduced waste. The residue was poured into crushed ice and stirred for 15 minutes. The aqueous solution was extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with a saturated aqueous solution of NaHC 3 (50 mL×2) and brine (25 mL).

The NhSO4 was dried and evaporated under reduced pressure to give a crude compound, 2, &lt;RTI ID=0.0&gt;&gt;&gt;&gt; Bite (ο) g). The crude compound was used in the next step without further purification. LC_ms (M+H)+=299. 〇〇Preparation of the product, s,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,8

F 149653.doc •113- 201107311 Add 7 g, 2·3 mm 〇1) to the solution at room temperature to add Cs2C03 (1.49 g, 4.6 mmol) to the solution in methanol, followed by the addition of methylamine hydrochloride ( 〇·78 g, 11·7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ . The crude compound was purified by column chromatography (6 〇 12 )) using 50% ethyl acetate petroleum ether as mobile phase to give 2-chloro-8- (4·fluorophenyl) as an off-white solid. Methyl-7,8-dihydro-5-pyrido[4,3-d]pyrimidin-4-amine (0.34 g, 49%). LC-MS (M+H)+=294.2. H NMR (400 MHz, DMSO-called: δ ppm 7.22-7.19 (2Η, m), 7.13-7.07 (2Η, m), 4.91 (1Η, m), 4.75 (1H, m), 4.12-4.08 (2H, m), 3.74 (1H, m), 3.05 (6H, S) 〇Preparation Jb 2-V-N-Ethyl·8_(4·Fluorophenyl)_7,8-Dihydro_5H_Pyloro[ 4,3_d]pyrimidine-4-amine

To a solution of the preparation j (0.35 〇g' 1.17 mm 〇l) in methanol was added diisopropylethylamine (0.30 g, 2.2 mmol), then ethylamine hydrochloride (0.113 g) , 1. 丨 7 mmol). The reaction mixture was stirred at room temperature 18 149653.doc • 114-201107311 hours. The solvent was removed under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude compound was purified by column chromatography (60-120 mesh) using 50% to 55% ethyl acetate in petroleum ether as mobile phase to afford 2 - 4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (0.16 g, 60%). LC-MS (M+H)+= 308. Preparation Jcl and JC2 2-Gas-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidinyl)_7,8-Dihydro-5H-^ D Nanhe [4,3 -d] ° dense. set

Diisopropylethylamine (0.60 g, 4.6 mm 〇1) was added to a solution of Preparation J (〇.70 g, 2.34 mmol) in methanol at room temperature, followed by (R) 3 fluoropyrrolidine ( 0.58 g, 4.6 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified eluting eluting eluting eluting ((S)-3-Fluoropyridinyl-1_yl)_7,8-dihydro·5H piperido[4,3-d]pyrimidine (0.90 g, 11% isomer!, 〇11〇g , 13% isomer 2). LC-MS (M+H)+=352.2. 4 NMR (400 MHz, DMSO-149653.doc • 115-201107311 d6): δ ppm 7.24 (2H, m), 7.13 (2H, m), 5.40 Πκ, m ), 4.12

(1H, d, J=14.8 Hz), 4.88 (1H, d, y=u.8 Hz), 4.l4-4.〇9 (2H

m), 3.91-3.81 (3H, m), 3.75-3.66 (2H, m), 2.5i_2 18 (2H m). Preparations Jdl and Jd2 2 -Gas- 8-(4--phenylene)-4-((R)-3-吼吼b each e定·i _ base)_7 8 5H- slightly sulphur[4,3 -d]pyrimidine

Diisopropylethylamine (0.60 g' 4.6 mmol) was added to a solution of Preparation J (0.70 g ' 2.34 mmol) in methanol φ ^ MeOH at room temperature, followed by (s) 3 fluoropyrrolidine (0.58) g, 4.6 mmol). The reaction mixture was stirred at room temperature for 18 hours. The bath was removed under reduced pressure, and the residue was purified by preparative H.sub.sub.2 (40% ethanol in hexanes) to give the product as an off-white solid. 4-((11)-3-Fluoropyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]°f. 〇(〇. 1〇〇 g ′ 12% isomer 1, 〇· 11 〇 g, isomer 2). LC-MS (M+H)+ = 352.2.

Jdl : 'Η NMR (400 MHz, OMSO-d6): δ ppm 7.24 (2H, m), 7.13 (2H, m), 5.40 (1H, m), 4.12 (1H, d, J = 14.4 Hz), 4.88 (1H, d, 7 = 14.4 Hz), 4.11 (2H, m), 3.94-3.89 (3H, m), 3.72- 149653.doc -116- 201107311 3.58 (2H, m), 2.20-2.01 (2H, m ).

Jd2 : !H NMR (400 MHz, DMSO-i/^): δ ppm 7.21 (2H m) 7.13 (2H, m), 5.39 (1H, m), 5.02 (2H, m), 4.02-3.97 (2H m ), 3.91-3.84 (4H, m), 3_73 (1H, m), 2.23-2.01 (2H, m). Preparation of Je 2 -gas- 8-(4-oxophenyl)-N,N-dimethyl- 7,8-diphos-5Η-α-n-butyl[4 3 d]pyrimidin-4-amine

Add Cs2C03 (1.49 g '4_6 mmol) to a solution of Preparation J (〇.7 g, 2_3 mmol) in decyl alcohol at room temperature, followed by dimethylamine hydrochloride (〇·95 g, 11.7 mmol). The reaction mixture was stirred at room temperature for a hour. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL), washed with water (25 mL), brine (25 mL), dried over anhydrous Na? Compound. The crude compound was purified by column chromatography (6 〇 _12 )) using 40% ethyl acetate in petroleum ether as mobile phase to give 2·fluorophenyl) as a pale white solid. Dihydrogen _5H_ travel taste [4,3_d] money _4_ amine (〇35 §, 49%). LC-MS (_) + = 3 〇 8.2. This compound was used in the next step without further purification. Preparation Jf -7,8-Dihydro-5H-piperido 2-gas-N-ethyl-8-(4-fluorophenyl)-N-methyl 149653.doc •117· 201107311 [4,3 -d]pyrazine bit _4·amine, νΤ\ cr

To a solution of the preparation J (0.7 g, 2.3 mmol) in methanol was added Cs2C03 (1_49 g, 4.6 mmol), then ethylethylamine hydrochloride (1.1 g, ll.Ymmol) . The reaction mixture was stirred at room temperature for 18 hours: The solvent was removed under reduced pressure, and the residue was purified ethyljjjjjjjjjjjjjjjjjjjj . The crude compound was purified by column chromatography (6 〇 _12 )) using a 50% solution of ethyl acetate (4) as the mobile phase to give the product as an off-white solid. -Fluorophenyl)-oxime-methyl-7,8-dihydro-5 heart-screaming and [4,3 collapsed to amine (.wg,

. LC-MS (M+H)+ = 322 2. This compound was not used in the next step. V Preparation Jg

Cr n 149653.doc 201107311 Add Cs2C03 (1.49 g, 4.6 mmol) to a solution of preparation j (〇.7 g, 2.3 mmol) in methanol at ambient temperature, followed by the addition of 3,3-difluoroaza Cyclobutane hydrochloride (0.60 g, 4.6 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude compound was purified by column chromatography (60-120 mesh) using 50% ethyl acetate petroleum ether elut Fluoroazetidin-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-5H-piperido[4,3-d]pyrimidine (0.42 g, 50%). LC-MS (M+H)+ = 355.2. This compound was used in the next step without further purification.

Preparation K 2,4_digas·8-(4-phenylphenyl)_7,8-dihydro-5H-pyrano[4,3_d]pyrimidine

CI was prepared in a manner similar to Preparation J (9) in the form of a pale yellow solid. LC-MS (Μ+ΗΓ=315.0. lH NMR (paste MHz, CDCl3) δ PPm 7·30 (2 Η, dd, J=2. 〇, 6 4 HZ), 7 17 (2H, dd, 〇, 6.4 Hz), 4.91 (1H, d, Hz), 4% (iH, d, J = 16 〇 Hz), 4.18-4.09 (3H, m). Preparation Ka 149653.doc -119- 201107311

Dinghao-1 -yl)-7,8-&gt;- Hydrogen melon α南和[4,3

Combine 2,4-dioxa-8-(4-phenylphenyl)-7,8-dihydro-5H-pyrano[4,3-d] 0 close-bit (袅菜#尺) (500 mg, 1.584 mmol) and 3,3-difluoroazetidin hydrochloride (308 mg, 2.377 mmol), and purified according to 潆 潆/^, yielding 2-chloro-8- (4 as a white solid) - gas phenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-511-11 benzo[4,3-(1]. (40〇111§, 1.075 mmol, yield 67.8%). LC-MS (M+H)+=372.0. 4 NMR (500 MHz, CDC13) δ ppm 7.22-7.34 (2 H, m), 7.12 (2 Η, d, ^=8.24 Hz), 4.63-4.85 (2 H, m), 4.46-4.64 (3 H, m), 4.04-4.17 (1 H, m), 3.91-4.04 (2 H, m). Preparation Kb 2-Gas-8-(4-Phenylphenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine

149653.doc -120- 201107311 Combination 2,4-dichloro- 8-(4-chlorophenyl)-7,8-dihydro-5H-. Chromium [4,3-d] pyrimidine (I dish #/〇 (500 mg, 1.5 84 mmol) and guanamine hydrochloride (16 〇 mg, 2.3 77 mmol), and purified according to Agrobacterium, 2 _ gas _ 8_(4-gas phenyl)-&gt; 1-mercapto-7,8-dihydro-511-'1 bottom '1 south and [4,3-(1]'&gt; dense 11 _ 4-amine (150 mg, 0.484 mmol, yield 30.5%). LC-MS (Μ+Η)+= 310.0. 4 NMR (500 MHz, CDC13) δ ppm 7.22-7.31 (2 Η, m), 7.13 ( 2 H,d, "7=8.55 Hz), 4.46-4.64 (1 H,m), 4.43 (1 h, • br. s.), 3.97-4.14 (1 H, m), 3.91 (1 H, d , 7=3.36 Hz), 3.09 (3 H,d, "7=4.88 Hz). Preparation Kc 2-Ga-8-(4-Phenylphenyl)-&gt;}, 1^-dimercapto-7 ,8-diaza-511-deutero[4,3_d]^.-4-amine

Combination 2,4-dioxa-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d] ° bite (farm field ruler) (500 mg, 1.5 84 mmol) and dimethylamine (2.0 M THF solution) (1.188 mL ' 2_ 3 77 mmol), and purified according to hydrazine/b. -N,N-Dimercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (400 mg, 1.234 mmo yield: 78%). LC-MS (M+H)+ = 324.0. NMR (500 MHz, CDC13) δ ppm 7.20-7.31 (2 H, m), 7.04-7.15 (2 H, m), 149653.doc • 121 - 201107311 4.70-4.89 (2 H,m), 4.17 (1 H , dd, "7=11.60, 5.49 Hz), 4.05 (1 H, t, J = 5.49 Hz), 3.87 (1 H, dd, J = 11.60, 5.49 Hz), 3.05-3.19 (6 H, m).

Preparation L 2,4-dioxa-8-(4-bromophenyl)-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine

The title compound was prepared in a similar manner to Preparation J as a pale yellow solid. LC-MS (Μ+Η)+=359·0. 4 NMR (400 MHz, CD3〇&gt;) δ ppm 7.52 (2H, d, 7=8.4 Hz), 7.22 (2H, d, 7=8.4 Hz ), 4.87 (1H, d, J=16.0 Hz), 4.30 (1H, t, J=4.6 Hz), 4.14 (1H, dd, J=4.6, 11.4 Hz), 3.95 (1H, dd, /=4.8, 11.6 Hz). Preparation La 8-(4-Phenylphenyl)-2-chloro-N-indenyl-7,8-dihydro-5 H-Bholyl[4,3_d] Mouth β-1,4-amine

Combination 8-(4-Molyphenyl)-2,4-diqi-7,8-dihydro-511-buck and [4,3_(1] pyrimidine (Nong #游L) (500 mg' ^389 Mmo1) with methylamine hydrochloride (141 149653.doc -122- 201107311 mg ' 2.083 mmol) ' and purified according to the agricultural ginseng, to give 8-(4-diphenyl)-2- s- Ν-methyl -7,8-Dihydro-5Η-0-[4,3-d] Methyl-4-amine (210 mg, 0.592 mmol, yield 42.6%). LC-MS (M+H)+ = 356.0. NMR (500 MHz, δ ppm 7.46 (2 H, d, /= 8.24 Hz), 7.13 (2 H, d, /=8.55 Hz), 4.43-4.71 (2 H, m), 4.09 (1 H, dd, "7=11.44, 4.12 Hz), 3.92-4.03 (1 H, m), 3.86 (1 H, d, /= 3.05 Hz), 3.00 (3 H, s).

Preparation M 2,4-diqi-7-(4-fluorophenyl)-5,7-dihydropyrano[3,4_d]

Cl Cl intermediate M(l) 2-hydroxy-2-phenylacetate

Ci

o A solution of pyrimidine-2,4,6-triol (10.0 g '78.2 mmol), DMF (12 mL) in POCIKIO volume) was heated under reflux for 15 h. Excess POCh was not evaporated under reduced pressure. The residue was poured into crushed ice. The solid was filtered and washed with water to give 2,4,6-trioxazole (8.0 g, 47%) as a yellow solid. This compound was used in the next step without further purification. 149653.doc -123- 201107311 Intermediate M(2) 2'4,6-Dioxy-5-(1,3-dioxoin-2-yl) 03⁄4. set

Ethylene glycol (4 〇 mL, 64.5 mmol) was added to the intermediate M (1) (5, 〇g, 23.6 mmol) in anhydrous benzene at ambient temperature, followed by the addition of p-toluenesulfonic acid (0.15). g, 0.87 mmoip The reaction mixture was heated under reflux for 20 hours. The reaction mixture was filtered and washed with warm benzene. Evaporated under reduced pressure' and purified by column chromatography (gum, 6 〇 〇 12 )) Purify the residue using a 1% by weight ethyl acetate petroleum ether solution as the mobile phase to obtain a gray

Color solid (4.5 g, 75%). LC-MS (Μ+Η)+=256·0. NMR (400 MHz, DMSO-required): δ ppm 9.6 (1H, s), 7.99 (1H, s), 7.98 (1H, s), 7.76-7.41 (3H, m), 7·23-7_13 (4H, m), 5.87 (1H, s), 5.33 (1H, dd, /=27, 8 Hz), 5·17 (1H, dd, "7=27, 8), 4.67 (4H, m), 3.72 (3H , s). ' Intermediate M (3)

g '15 at a concentration of 中间°C to the intermediate M(2) (4_0 • 6 mmol) in anhydrous ethyl sulphate to add desertified 4-fluorobenzyl (75.2 mL, 18 mm〇i, 149653. Doc -124- 201107311 0.25 M THF solution). The reaction mixture was allowed to reach room temperature and was stirred for 4 hours. The reaction mixture was quenched with saturated aqueous solution of acetic acid. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (50 mL×2). The combined organic layers were washed with water, dried over anhydrous Na. The crude compound was purified by ___, using 1.4% ethyl acetate stone oil ether as mobile phase to give 2,4-dichloro-5-(1,3-dioxolanyl) as an off-white solid. -6-(4-Gasbenzyl)pyrimidine (2.2 g '43 1〇/〇). [ο· (M_H)+= 327.0. NMR (400 MHz, DMSO-m): § ppm 7·26 (2H, m), 7.10 (2H, m), 6.19 (1H, s), 4.25 (2H, s)5 4.19 (2HS m), 4.02 ( 2H, m). ' Intermediate M(4) (2,4-Dichloro-6-(4-fluorobenzyl)n-Bite_5_yl)methanol ci

To a solution of 3 χ 2 〇g, 6Q7 in THF was added 6 N aqueous hydrochloric acid at room temperature over a period of 5 min. The reaction mixture was heated under reflux for 1 hour. The reaction volume was reduced to -half and ether. (5 〇 mL x 2) extraction solution. The combined organic layer was washed with water (50 mL), brine (5 mL), dried over anhydrous Dissolve in methanol and cool to 〇. 〇 Add sodium nitrate (0.234 g) to the reaction mixture. Bring the solution to a temperature of 149653.doc -125-201107311 and stir for 1 hour. The reaction mixture was quenched and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (5··················· Evaporation under pressure to obtain a crude compound. The crude compound was purified by column chromatography (EtOAc, 60-120 mesh) using a petroleum ether solution of ethyl acetate as a mobile phase to give an oily liquid ( 2,4_ dichloro_6-(4.fluorobenzoquinone Pyrimidine _5•yl) sterol (1 〇g, 58%). lC_ms (Μ+Η)+=488.1 ο Ή NMR (300 MHz, CDC13): δ ppm 7.25 (2H, m), 7.01 (2H, m), 4.82 (2H, m), 4·27 (2H, s).

Preparation M 2,4-diqi-7-(4-fluorophenyl)_5,7•dihydrofuro[3,4_d]pyrimidine

Add Cs2CO3 (0.4 g, 3.48 mmol) to a solution of the intermediate Μ(4)(ι·〇g, 3:48 mm〇i) in anhydrous benzene (1 mL) under EtOAc. Lead tetraacetate (0.3 g, 3.48 mmol) (the color of the reaction mixture changed from colorless to brown). The reaction mass was refluxed for 18 hours using a Dean Starck apparatus. The reaction mixture was filtered through a pad of celite and washed with diethyl ether. The filtrate was evaporated under reduced pressure and the residue was diluted with diethyl ether. The organic solution was washed with water (25 mL×2), sat. NaH.sub.3, and brine (1 mL), dried over anhydrous Na.sub.2, and evaporated. By 149653.doc •126· 201107311

Combiflash, using a 0.9% ethyl acetate petroleum ether solution as the mobile phase to purify the crude compound to give 2,4-dichloro-7-(4-oxobenzene) as an oily liquid.

Base)-5,7-dihydro-fusino[3,4-d]a bite (0.250 mg, 30°/c&gt;) QLC-MS (Μ+Η)+=485·0. 4 NMR ( 400 MHz, methanol - as): 5 ppm 7 48_ 7.44 (2H, m), 7.16-7.12 (2H, m), 6.15 (1H, s), 5.40 (iH, dd •7=13.6 Hz), 5.27 (1H , dd, /=13.6). Preparation Ma 2- gas-7-(4-1phenyl)-N-mercapto-5,7-dihydrogen. husband. South and [3,4·^] spray.定_ 4-amine nnh

2,4-Dichloro-7-(4-fluorophenyl)-5,7-dihydrofuran[3,4_d] was combined. Separation (preparation M) (250 mg, 0.877 mmol) and decylamine hydrochloride (89, 1.315 mmol), and purified according to preparation la, to give 2- _7_(4 fluorophenyl)-N- Mercapto-5,7-dihydrofuranto[3,4-d] mouth bite 4-amine (Mg mg '0.533 mmol, yield 60.8%). LC-MS (Μ+Η)+=28〇 〇. NMR (500 MHz, MeOD) δ ppm 7.31-7.44 (2 Η, m) η 〇5 7.17 (2 Η, m), 5.80-5.95 (1 Η, m), 4.94-5.21 (2 Η, m), 2 93 3.07 (3 Η, m). Preparation Mb 2-Gas-N-Ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine 149653.doc -127- 201107311 4-amine (

NH

Combination of 2,4-dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (1 25 mg '0.438 mmol) with ethylamine Hydrochloride (53.6 mg, 0.658 mmol), and purified according to the preparation to give octane-^^ethyl-7-(4-fluorobenzyl)-5,7-dihydropurine and [3, 4-d]0^ bite-4-amine (38.17 mg, 0.130 mmo yield 29.6%). LC-MS (Μ+Η)+=294·0. 'H NMR (500 MHz, CDC13) δ ppm 7.24-7.38 (2 H, m), 6.92- 7.08 (2 H, m), 5.73-5.98 (1 H, m), 4.83-5.21 (2 H, m) , 3.36-3.63 (2 H, m), 1.13-1.28 (3 H, m) 〇Preparation Mcl and Mc2 2-Ga-7-(4-|L Phenyl)-4-((S)-3- Fluorine.Byrrolidine_ι·yl)_5,7-dihydrofuro[3,4-d]pyrimidine

Combining 2,4-dioxa-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (preparative M) (125 mg, 0.438 mmol) with (8)_3_ Flurpyridine hydrochloride 149653.doc • 128· 201107311 (83 mg, 0.658 mmol), and purified according to Preparation Ha to give 2··········· -3-Fluoropyrrolidine-l-yl)-5,7-dihydropurine and [3,4-d]pyrimidine. (Mci, diastereomer 1, first eluted) (49 mg, 0.145 mmol, yield 33.1%). LC-MS (M+H)+ = 338.0. 'Diastereomer 2, second eluted) (4 〇 mg, 〇.! J 8 mmol, yield 27.0%). Lu LC-MS (M+H)+=338.0. The relative stereochemistry of Me/ and Mc2 was not determined. Preparation Md 2-Oxo-4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)_5,7·dihydrofuro[3,4-d Pyrimidine

N

To a preparation of M (0.05 g, 0.176 mmol) in methanol, isopropylethylamine (0.045 g, 0.30 mmol) was added at room temperature, followed by the addition of 3,3-difluoro nitrogen Heterocyclic butane hydrochloride (〇·〇3 g, 0.193 mmol). The reaction mixture was stirred for 1 Torr at a, ra ^ gan to warm. The solvent was removed under reduced pressure, and the residue was purified using EtOAc EtOAc EtOAc (EtOAc) _4 149653.doc -129- 201107311 Azetidin-1-yl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (0.035 g , 46%). LC-MS (M+H)+ = 342.2. Preparation Me 2 -Chloro-7-(4-milophenyl)-4-((S)-2-methyl^Bilobit-1-yl)-5,7- A wind bite and [3, 4-d] pyrimidine bite

2,4-Dichloro-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) with (S)-2-decylpyrrolidin The p-toluenesulfonate is reacted as described in the preparations Hpl and Hp2 to give 2-gas-7-(4-fluorophenyl)-4-((S) as a mixture of two diastereomers. -2-mercaptopyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation Me). ZC-MS (Μ+Η)+=334·1. Preparation Mf 2-Gas-N-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine- 4-amine

149653.doc -130- 201107311 to 2,4-dioxa-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine (Preparation M) (150 mg, (8)·1_cyclopropylethylamine hydrochloride (128 mg, 1.052 mmol) and DIEA (368 pL, 2.105 mmol) were added in THF (263 1 pL). The mixture was heated at 40 ° C for 2 hours and stirred at room temperature overnight. The mixture was concentrated and purified by a celite column chromatography to give the mixture of two diastereomers as a solvent. (4_Fluorophenyl)_5,7•Dihydrofuro[3,4_d] Mouth-4-amine (preparative) (25 mg, 0.075 mmol, yield 14.24%). LC-MS (Μ+Η)+=334·1. Preparation Mg 2-gas-7-(4-fluorophenyl)-4-((R)-3-fluoro.pyrrolidin-1-yl)·5,7-dihydrofuran[3,4 -d]pyrimidine

F 2,4-monolac-7-(4-fluorophenyl)-5,7-dihydro Dfu-[3,4-d] mouth bit (preparative M) and (R)_3-fluoro Pyrrolidine hydrochloride reacts as described in Preparation xa to give 2-chloro-7-(4-fluorophenyl)-4-((R)-3-fluoroindol-1-yl)-5 , 7-Dihydrofuro[3,4-d]pyrimidine (Preparation Mg). LC-MS (M+H)+ = 338.1. Towel NMR (400 MHz, CDC13) δ ppm 7.33-7.47 (m, 2 H) 7.00-7.14 (m, 2 H) 5.83-5.97 (m, 1 H) 5.54 (dd, J=ll.33, 149653.doc -131 - 201107311 3.53 Hz, 1 Η) 5.36-5.49 (m, 2 Η) 3.88-4.00 (m, 1 Η) 3 65- 3.88 (m,3 Η) 2.30-2.52 (m,1 Η) 2.02-2.20 (m, 1 Η) 〇Preparation Mh 2-Qi-4-((28,6 ft)-2,6-dimethyl 1^-morphinyl)_7_(4_Fluoro 1 stupyl)_5 7 II Hydrogen bites. Nanhe [3,4-d] bite

2,4-·1 gas- 7-(4-air-based)·5,7-dihydroanthracene [3,4-d] mouth bit (preparative M) and (2R,6S)-2, 6-Dimethylmorpholine reacts as described in Preparation xa' to give 2-gas-4-((2S,6R)-2,6-diamidino N-morpholinyl)-7-(4- Fluorophenyl)_5,7-dihydrofuro[3,4-d]pyrimidine (preparation Mh). LC-MS (Μ+Η)+=364·2. NMR (500 MHz, CDC13) δ ppm 7.39 (dd5 J=8.70, 5.34 Hz, 2 H) 7.07 (t, J=8.70 Hz, 2 H) 5.90 (br. s·, 1 H) 5.34-5.42 (m, 1 H) 5.24-5.34 (m,1 H) 4.14 (q, J=7.02 Hz, 2 H) 3.67 (ddd, J=l〇.38, 6.41, 2.44 Hz, 4 H), 1.20 (m,6H) .

Preparation N 2,4-dioxa-8-phenyl-6,8-dihydro-511-'1 benzo[3,4-&lt;1] shouting 149653.doc •132- 201107311

Cl

Intermediate N(l) 2-Phenyl-2-phenylacetate EtOOC oh _ ο,·Star 1 〇 Knocking time to 2-hydroxy-2-phenylacetate (25〇g, 164.3 mmol) Concentrated sulfuric acid was added to the cooled solution in ethanol (1). The reaction was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (250 mL). The organic solution was washed with a saturated aqueous solution of NaHCO3 (2 mL mL), water (1 mL), and brine (1 mL), dried over anhydrous Na? Ethyl 2-hydroxy-2-phenylacetate (24, 5 g, 83%). The crude compound was used in the next step without further purification. LC-MS (M+H20)+ = 198.2. 'H NMR (400 MHz, DMSO-^6): δ ppm 7.41-7.28 (5H, m)s 6.04 (1H, d, J = 4.0 Hz), 5.11 (1H, d, J = 4.0 Hz), 4.13 ( 2H, m), 1.13 (3H, t, «/=7.2 Hz). Intermediate N(2) 4-(2-Ethoxy-2-oxo-1-phenylethoxy)but-2-enoate

EtOOC^^^^O COOEt 149653.doc •133· 201107311 Add silver oxide (66.75 g, 288_5 mmol) to a solution of the intermediate N(l) (20.0 g, 110.9 mmol) in hexane. Then, add sulfuric acid town (2.66 g '220 mmol). The reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled to &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The resulting solution was mixed for 3 days. The reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give ethyl 4-(2-ethoxy-2-?-oxyphenylethyloxy)but-2-enoate as an oily liquid (20.0 g, 62.5%). LC-MS (M+H20)+=3 10.2. NMR (400 MHz, DMSO-^): δ ppm y.42-7.35 (5Η, m), 6.90 (1H, m), 6.05 (1H, m)5 5.09 (1H, s)5 4.26 (2H, m) , 4.16 (4H, m), 1.21 (3H, t' "/= 7.2 Hz), 1.13 (3H, t, *7 = 7.2 Hz). Intermediate N(3) 4·(2-ethoxy-2-oxo-1-phenylethoxy)butyric acid ethyl ester

Palladium on carbon (丨0%, w/w) was added to the bath of the intermediate N(2) (2〇.〇g, 68 41 mm〇1) in ethanol at room temperature. The reaction mixture was hydrogenated under a hydrogen balloon pressure for 30 hours. The reaction mass was filtered through a pad of Celite® and washed with ethanol. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (EtOAc EtOAc EtOAc EtOAc Ethyl 2-ethoxy-oxo-methoxy-1-phenylethoxy)butyrate (12. g, 59 5%). lC_ms (m+h)+= 149653.doc •134· 201107311 295.2 〇1 Η NMR (400 MHz, OUSO-d6): δ ppm 7.41-7.27 (5H, m), 4.96 (1H, s), 4.07 (4H , m), 3.62 (1H, m), 3.49 (1H, m), 2.36 (2H, m), 179 (2H, m), 1.15 (6H, m). Intermediate N(4) 3_Sideoxy·_2-Benzyltetrahydro.-2H+-Pin-4-carboxylic acid

To Buj ((3. The reaction mixture was allowed to reach room temperature and stirred for 1 hour. The reaction mixture was quenched with water and evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL). The organic layer was washed with water (1 mL mL 2), brine (EtOAc) and evaporated to dryness. The crude compound was purified by column chromatography (tank '60-120 mesh)' using a 50% ethyl acetate petroleum ether solution as a mobile phase to give a 3-hydroxyl-2 phenyl group as an oily liquid. Hydrogen-2H-piperidin-4-decanoate (6.0 g, 59.4%). LC-MS (M+H)+=249.2. 4 NMR (400 MHz, DMSO-state: δ ppm 11.81 (1H, s), 7.36 (5H, m), 5.20 (1H, s), 4.23 (2H, q , J=7.2.0 Hz), 3.71 (1H, m), 3.67 (1H, m), 2.36 (1H, m), 2.32 (1H, m), 1.29 (3H, t, "7=7.2 Hz). Intermediate N(5) 8-phenyl-5,6-dihydro-1H-furo[3,4-d]pyrimidine-2,4(3H,8H)-dione 149653.doc -135- 201107311

To a solution of the intermediate N(4) (6.0 g, 24.16 mmol) in ethanol was added i-BuOK (6.76 g, 60.41 mmol), followed by urea (3_62 g, 60·41 mmol). The reaction mass was heated under reflux for 18 hours. The reaction mixture was quenched with water and the solvent was evaporated evaporated. The residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (1 mL mL), brine (EtOAc) The crude compound was purified by column chromatography (EtOAc EtOAc EtOAc (EtOAc) And [3,4-d]pyrimidine-2,4(3H,8H)-dione (3.0 g, 50.8%). LC-MS (Μ-Η)+=243·2. NMR (400 MHz, OMSO-d6): δ ppm 11.10 (1Η, s), 10.57 (1H, s), 7.42- 7.39 (3H, m), 7.32 (2H, m), 5.32 (1H, s), 3.71 -3.56 (2H, m), 2.3 8 - 2.2 7 (2 H,m ) 〇

Preparation N 2S4-dichloro-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine

A solution of the intermediate N(5) (2.〇 g '8 18 mm〇1) and a catalytic amount of dMF^p〇C13 (io volume) was heated under reflux for 18 hours. Under decompression J49653.doc •136· 201107311 Evaporate excess POC13. The residue was poured into crushed ice and mixed for 15 minutes. The aqueous solution was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with a saturated aqueous solution of NaHC 3 (50 mL×2) and brine (50 mL)

The NasSO4 was dried and evaporated under reduced pressure to give y,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, g, crude LC-MS (M+H)+ = 281 δ. Preparation Ήα 2-chloro-indole-methyl-8-phenyl-6,8-dihydro-5Η-pyrano[3,4-d ]How to bite _ 4-amine HN〆

Diisopropylethylamine (1.83 g, 14-2 mmol) was added to a solution of the product N (2.1 g, EtOAc). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified eluting with EtOAc EtOAc (EtOAc) N-Mercapto-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-4-amine (0.7 g, 35.7%) °LC-MS (M+H) += 276.0 〇*Η NMR (400 ΜΗζ, DMSO-state: δ ppm 7·49 (1Η, m), 7.36-7.31 (3Η, m), 7.25-7.23 (2Η, m), 5.45 (1Η, s) , 4.0 (1H, m), 3.79 (1H, m), 2.87 (3H, d, /=4.4 Hz), 2.55 (1H, m), 2.44 (1H, m) ° 149653.doc -137· 201107311 Preparation ο 2'4-monochloro_8_(4_fluorophenyl)·Μ二气_5Η派.南和[3,心^啦啶

F intermediate 0 (1;)

Ethyl 2-(4-fluorophenyl)_2-hydroxyacetate EtO〇C, 〇H over 1 _ to 2-(4-fluorophenyl)-2 thioglycolic acid (5.0 g, 29.4 mmol) Concentrated sulfuric acid was added to the cold portion of the ethanol (m.). The reaction mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (25 ml). The organic solution was washed with an aqueous solution (25 mL 2) of water (2 mL), a saline solution (1 mL), dried over anhydrous Na 2 S 4 and decompressed, and (4) was in the form of a crude compound (oily liquid). -(4-Fluorophenyl)_2-hydroxyacetic acid ethyl ester (5 〇g, 90 〇 /.). The crude compound was used in the next step without further purification. π. (Μ+Η20) =216 〇*H NMR (400 MHz, DMSO-^): δ 7.43- 7.46 (2H, m), 7.17-7.20 (2H, m), 6.11-6.13 (1H, m), 5.14 (1H, d, / = 5.20 Hz), 3.35-4.13 (2H, m), 1.12-1.15 (3H, m) Intermediate 0(2) 149653.doc -138- 201107311 4-(2-Ethoxy-1-(4-fluorophenyl)_2 _Sideoxyethoxy)butyl-2-enoate

EtOOC, a π rnnPt

Add silver oxide (9"g, 39 3 mm〇l) to a solution of the intermediate 〇(1)(3.〇g, 15 1 mm〇1) in hexane at room temperature, followed by the addition of magnesium sulfate. 8 • g ' 3 · 0 mmol). The reaction mixture was heated under reflux for a few hours. The reaction mixture was cooled to Ot: and silver oxide (9.7 g, 39.9 mmol) was added, followed by ethyl 4-bromocrotonate (4.3 g, 22.7 mmol). The resulting solution was mixed for 3 days at room temperature. The reaction mass was filtered through a pad of Celite (EtOAc) and washed with ethyl acetate. Evaporation of the filtrate under reduced pressure gave 4-(2-ethoxy-1-(4-fluorophenyl)-2-oxoethoxyethoxy)but-2-enoate as an oily liquid (3 .〇g, 90%). LC-MS (M+H20)+ = 328.2. NMR (400 MHz, CDC13): δ ppm 7.42-7.45 (2H, m), 7.04-7.26 (2H, m), 6.95 (1H, m), ♦ 6.12 (1H, m), 4.89 (1H, s), 4.13-4.28 (6H, m), 1.30 (3H, t, •7=7.20 Hz), 1.26 (3H, J=6.8 Hz) 〇Intermediate 0(3) 4-(2-Ethoxy-1 -( Ethyl 4-fluorophenyl)-2-oxoethoxyethoxy)butyrate

To a solution of the intermediate hydrazine (2) (3.0 g, 9.6 mmol) in ethanol was added palladium/carbon (10 ° / 、, W/W) at room temperature. The reaction was mixed under a hydrogen balloon pressure for 149, 65. doc • 139 · 201107311 for 30 hours. The reaction material was passed through a bed of diatomaceous earth (CeH @^避&gt; and washed with ethanol. The solvent was removed under reduced pressure and subjected to column chromatography (gum, 6 〇 12 ))) using 5% acetic acid The oily solution was used as a mobile phase to purify the residue to obtain 4_(2-ethoxyl-1(4fluorophenyldifluoride oxyethoxy)butyric acid ethyl ester (3.〇) in the form of an oily liquid. g, 63%). LC_Ms (μ: η) + = 313.2. * NMR (400 MHz, CDCl3): δ ppm 7 π? 46 lang, m), 7.05-7.09 (2H, m), 4.84 (1H, s)&gt; 4.10-4.23 (4H} m)^ 3-59-3.63 (1H, m), 3.42-3.53 (1H, m), 2.47 (2H, t, J=7.6 Hz), 1.99 (2H, t , J=7.6 Hz), 1.22-1.32 (6H, m) 〇' Intermediate 0(4) 2-(4-Fluorophenyl)-3-oxo-oxytetrahydro-2H-pyran-4-decanoic acid乙西

F / /BuOK (2.1 g, 19.0 mmol) was added to the cooled solution of the intermediate (3) (3. g, 9.6 mm 〇1) in THF. The reaction mixture was allowed to reach room temperature and stirred for 1 hour. The reaction mixture was quenched with water and evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL). The organic layer was washed with water (1 mL EtOAc) (EtOAc)EtOAc. The crude compound was purified by column chromatography (Shishijiao 60-120 mesh) using a 50% ethyl acetate petroleum ether solution as a mobile phase to give 2_(4-fluorophenyl)3_ as an oily liquid.

Ethyl tetrahydro-2H-pyran-4-carboxylate (1.0 g, 55%). LC-MS 149653.doc -140- 201107311

(M+H)+=267.1. 4 NMR (400 MHz, DMSO-m)·S }' 0 ppm 11-81 (1H, s), 7.22-7.42 (2H, m), 7.12-7.20 (2H, m ), 5 23 (1H, s), 4.22 (2H, q, *7 = 7.2 Hz), 3.87-3.88 (1H, m), 3 69 3.84 (1H, m), 2.34-2.35 (1H, m), 2.30-2.33 (1H, m),! 27 (3H, t, *7 = 7.2 Hz). Intermediate 0(5) 8-(4-1 phenyl)-5,6-dihydro-1 Η-D carboxy[3,4_d] n 唆 _ 2,4(3Η,8Η)-dione

To a solution of intermediate 0 (4) (0.30 g ' 1.12 mmol) in ethanol was added i-BuOK (0.253 g, 2.2 mmol), followed by urea (〇_135 g, 2.2 mmol). The reaction mass was heated under reflux for 18 hours. The reaction mixture was quenched with water and the solvent was evaporated evaporated. The residue was diluted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL×2), brine (1 mL) and dried over anhydrous The crude compound was purified by column chromatography (EtOAc, EtOAc (EtOAc): Dihydro-1H_pyrano[3,4_d]pyrimidine_2,4 (3H,8H)-^^ (0.150 g, 40%) 〇LC-MS (MH)+=263.1 〇»H NMR (400 MHz , DMSO-^): δ ppm U.14 〇Η? s)&gt; 1〇5? Face 141· 149653.doc 201107311 (1H, s), 7.35-7.36 (2H, m), 7.22 (2H, m) , 5.34 (iH s) 3.66-3.71 (1H, m), 3.58-3.64 (1H, m), 2.33 (2H, m). ’

Preparation O 2,4-dioxa-8-(4-fluorophenyl)-6,8-dihydro-511_piperido[3,4-d]pyrimidine

A solution of intermediate 0 (5) (0.30 g' i.i mmol) and a catalytic amount of DMf in pocikio volume) was heated under reflux for 18 hours. Excess POCI3 was evaporated under reduced pressure. The residue was poured into crushed ice and simmered for 5 minutes. The aqueous solution was extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with aq. EtOAc EtOAc (EtOAc) Phenyl)-6,8-dihydro-5H-piperacino[3,4-d]pyrimidine (0.20 g, crude). LC-MS (Μ+Η)+=299·〇. Preparation Οα 2-Gas-Ν-Ethyl-8-(4-fluorophenyl)-6,8-dihydro-5Η-piperido[3,4-d]pyrimidine-4-amine

149653.doc • 142-201107311 Add isopropylethylamine (〇30 g, 2 2 mm〇) to a solution of the preparation 〇 (〇_35 g, M mm〇i) in methanol at room temperature. i), followed by the addition of the ethylamine salt 3 夂 salt (0·113 g 'mmGi). The reaction mixture was stirred at room temperature, the solvent was removed under dust removal, and the residue was purified by column chromatography (10)_manufacturing using 35% ethyl acetate (4) solution as the mobile phase. 2_气_N_Ethyl_8_(4_fluorophenyl), 8_dihydro-5H-Nymphoteric [3,4_d]n bite · 4_amine (〇) 15 § 'Coarse. Μ-· (M+H)+=308.2.0 Preparation Oh Chlor-8-(4-fluorophenyl)_N_methyl·6,8 二气_5Η·嗔[[,4-d]pyrimidine_4-amine

To a solution of the preparation 0 (0.20 g, 0.61 _〇1) in decyl alcohol, diisopropylethylamine (0.172 g, l3 mm 〇i) was added at room temperature, followed by the addition of ethyl methylamine hydrochloride. Salt (0_47 § '0.81 job 1). The reaction mixture was searched for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography ('m.), using 40% ethyl acetate ethyl ether solvent as mobile phase to afford 2 - Ethyl _8_(4_敦笨基)_ 义 methyl-M-dihydro_5H "bottom [3,4_d]. dense. glacial amine (〇〇2〇^, coarse). LC-MS (Μ+Η)+=322·2. 149653.doc -143- 201107311 Preparation Ocl and 0c2 2-chloro-8-(4-phenylphenyl)-4-((R)_3_iDtbB each bite base ^, 8_Dinitro 5H-piperazino[3,4_d]pyrimidine, a witch

To a solution of Preparation 0 (0.60 g '2.1 mm 〇i) in decyl alcohol was added diisopropylethylamine (0-516 g, 4.6 mm 〇l), followed by addition) _ 3-fluoropyrrole at room temperature Pyridine (0.301 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by preparative </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -yl)-6,8-dihydro-5H-piperacino[3,4-d]pyrimidine (0.110 g '40% isomer 1 '0.109 g, 40% isomer 2). LC-MS (M+H)+ = 352.0.

Ocl: *H NMR (400 MHz, DMSO-^): δ ppm 7.36-7.36 (2H, m), 7.16 (2H, m), 5.50 (2HS d, J=8.40 Hz), 5.35 (1H, s), 3.58-3.98 (7H, m), 3.24-3.34 (1H, m), 2.78 (1H, m), 2.04-2.28 (2H, m).

Oc2: NMR (400 MHz, DMSO-m): δ ppm 7.19-7.33 (2H, m), 7.15-7.20 (2H, m), 5.34 (1H, m), 5.40 (1H, m), 3.91-4.10 ( 2H, m), 3.75-3.90 (2H, m), 3.69-3.75 (2H, m), 3.05 149653.doc 144- 201107311 (2H, t, /= 5.20 Hz), 2.01 (2H, d, Hz). Preparations Odl and Od2 2-Gas-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidinyl)_6 8-dihydro 5H-Nantido[3,4_d]

To a solution of the preparation 0 (0.60 g, 2 > 1 mm 〇 1) in methanol, diisopropylethylamine (0.516 g, 4 6 mm 〇1) was added at room temperature, followed by the addition of 〇3·fluoride Pyrrolidine (0.301 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified eluted eluted eluted elut elut elut eluting Dihydro-5H-piperacino[3,4-d]pyrimidine (0.102 g '39./〇 isomer 1, O. lii g, 40% isomer 2). LC-MS (M+H)+ = 352.0. 〇 dl: 'Η NMR (400 MHz, DMSO-J5): δ ppm 7.36-7.36 (2H, ^), 7.16 (2H, m), 5.50 (2H, d, J=8.4 Hz), 5.35 (1H, s ), 3.58-3.98 (7H, m), 3.24-3.34 (1H, m), 2.78 (1H, d, J = 8.4 Hz), 2.04-2.28 (2H, m). 〇d2: NMR (400 MHz, DMSO): δ ppm 7.19-7.33 (2H, m), 7.15-7.20 (2H, m), 5.34 (1H, m), 5.40 ( (1H, m), 3.91- 149653 .doc •145· 201107311 4.10 (2H, m), 3.75-3.90 (2H, m), 3.69-3.75 (m, 2H), 3.05 (2H, t, J=5.20 Hz), 2.01 (2H,d,/ =8.0 Hz).

Preparation P 2,4-Dichloro-7-(4-phenylphenyl)-6,7-dihydro-5/fluorene-cyclopenta[d]pyrimidine

Intermediate P(l) 1-Gas_4 - Cyclodecyl Benzene

To a solution of 1 M phenylphosphonium bromide (149 mL, 149 mmol) was added EtOAc (1. After the addition, the solution becomes warm. The reaction mixture was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and quenched with 10 g of ice. Add 6 N hydrochloric acid solution until the temple is completely dissolved. Add ether. The organic layer was separated and the aqueous phase was extracted with diethyl ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogensulfite, saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS (M+H)+ = 179.2. A NMR (500 MHz, CDC13) δ ppm 7.27-7.39 (4H, m), 6.19 (1H, s), 2.66-2.74 (2H, m), 2.52-2.61 (2H, m), 2.01-2.12 (2H, m). 149653.doc •146· 201107311 Intermediate P(2) 2-(4-Phenylphenyl)cyclopentanium

A mixture of formic acid (60 mL, 84 mmol) and hydrogen peroxide (15 mL, 84 mmol) was warmed to 40 &lt;0&gt;C for 10 min. The resulting solution was carefully added to 1- gas-4-cyclopentenylbenzene (15 g ' 84 mmol) with stirring. The two phase system was initially mixed at room temperature. After a period of time, a self-heating reaction occurs and the temperature rises to about 50 °C. The reaction mixture was stirred at room temperature for 1 hour. LC/MS analysis of the reaction mixture showed the disappearance of the starting material and formation of the product. The reaction mixture was quenched by the careful addition of saturated sodium bicarbonate solution. Ether was added and the reaction mixture was shaken vigorously. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and dried. The solvent was removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting eluting eluting . LC-MS (Μ+Η)+=195·2. NMR (500 MHz, CDC13) δ ppm 7.21-7.37 (2Η, m), 7.11 (2H, d, J=8.5 Hz), 3.25 (1H, dd, J=11.6, 8.5 Hz), 2.44 (2H, d, J = 6.1 Hz), 2.15-2.31 (1H, m), 1.96-2.15 (3H, m), 1.78-1.95 (1H, m). Intermediate P(3) 7-(4-Phenylphenyl)_6,7-dihydrocyclopenta[e;][1,3]oxazine-2,4(3 Dan,5/^_dione 149653 .doc -147· 201107311

Stir 2_(4_气笨基)戍戍_(78〇g' 40"_〇1) and an inert atmosphere (7·61 g, 72"_〇ι) in a high pressure vessel at 58t: The solution was 1 hour. The temperature rose to 13 〇. (: and the reaction mixture was stirred for another 2 hours. After cooling to room temperature, the reaction mixture was solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted twice. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated. The solvent was removed in vacuo, and the oily residue was purified by a gelatinous tube (4) to give 7-(4-chlorophenyl)_6,7_2 Hydrocyclopenta(5)π,3]pyridazine_ '(-ketone (5.4 g ' 20.48 mmol ' yield 51 1%). LC_ MS (Μ+ΗΓ=264.2 ο Ή NMR (5〇〇MHz, CDC13) δ ppm 7.32 (', J 8.5 Ηζ), 7.12 (2Η, d, *7=8.5 Ηζ), 4.15-4.25 (1Η, m), 2.56-2.93 (4Η, m). Intermediate Ρ(4) (chlorophenyl) )_6,7-dihydro·1/f_cyclopenta(4)pyridinium _2 4 ie, 5 outside

CI in a high pressure vessel under the loot sandalwood 7-(4-phenylphenyl)·6,7-dihydrocyclopentane 149653.doc 201107311 and [e][l,3]° 嗓-2,4(3i /, 5/7)-Dione (5·4 g, 20.48 mmol) in concentrated EtOAc (5 mL, EtOAc) A white precipitate formed during heating. The solvent was removed in vacuo to give 7-(4-phenylphenyl)-6,7-dihydro-1--cycloindole[d] as an off-white solid.密定, 2,4 (3//&quot;, 5/f)-dione (4.9 g, 18.65 mmol, yield 91%). LC-MS (Μ+Η)+=263·2. Towel NMR (500 MHz, DMSO-A) δ ppm 7.37 (2H, d, /=8.2 Hz), 7.19 (1H, d, J = 8.5 Hz), 4.16 (1H, d, •/=5.2 Hz), 3.79 (1H, br s), 3.17 (1H, s), 2.51 (2H, d, J = 1.8 Hz), 1.75-1.85 (1H, m).

Preparation P 2,4-digas-7-(4-chlorophenyl)-6,7-dihydro-5//-cyclopenta[d]

Cl

7-(4-Chlorophenyl)-6,7-diindole-li/-cyclopenta[d] mouth. a mixture of -2,4(3//,5//)-dione (4.7 g, 17.89 mmol), P0C13 (53.4 mL, 573 mmol) and dimethylaniline (18.26 mL, 143 mmol) at 11 〇 . Underarm heating up overnight. The reaction mixture was poured into an ice-containing beaker. The inner wall of the reaction vessel was washed with DCM. Once the ice has completely melted, the organic layer is separated and the aqueous layer is extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give 2,4-di-s--7-(4-chlorophenyl)-6,7-dihydro-5/ί-cyclopentane And [d] mouth pyridine (1.2 g, 4.01 mmo yield 22.39%). LC-MS (M+H)+ = 299.0. 149653.doc -149· 201107311 H NMR (500 MHz, CDCI3) δ ppm 7.41-7.99 (2H, m), 7.09 (2H, d, 7=8.5 Hz), 4.41 (1H, t, ./=8.4 Hz) , 2.94-3.18 (2H, m), 2.73 (1H, dt, *7=8.9, 4.5 Hz), 2.15-2.33 (1H, m). Preparation P a 2-gas·7-(4-phenylphenyl)-iV, 7V-dimethyl-6,7-dihydro-5-5-cyclopenta[d]. Melidine-4-amine

Stir 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5 open-cyclopenta[d]pyrimidine (200 mg, 〇_668 mmol) and excess 2 at room temperature A solution of the guanamine (3 34 mL, 6·Μ mmol) in MeOH (4 mL) The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography to afford &lt;RTI ID=0.0&gt;&gt; Cyclopenta[d]pyrimidin-4-amine (98 mg '0.318 mmol' yield 47.6%) » LC-MS (M+H)+=308.1. Preparation Pb 2-chloro-7-(4-phenylphenyl)_4_(3,3·difluoroazetidinyl),6,7-dihydro-5 ugly-cyclopenta[d] Pyrimidine

CI 149653.doc -150- 201107311 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5cyclopenta[d]pyrimidine was stirred at room temperature. Ding (325 mg, 1.085 mmol), 7V-ethyl-iV-isopropylpropan-2-amine (0.945 mL, 5.42 mmol) and 3,3-dioxazepine hydrochloride (281 mg, 2.170) Methyl acetate in MeOH (5 mL) for 1 h. The solvent was removed in vacuo and the crude was purified eluted eluted eluted eluted eluted eluted Base)-6,7-dihydro-5//-cyclopenta[d]. (70 mg, 0-197 mmol, yield 18.12 ° / 〇). • LC-MS (Μ+Η)+=356·1. Preparation Pc 2 -gas-7-(4-phenylphenyl)-7V~indolyl-6,7-dihydro-5//-cyclopenta[d]

4-amine ^NH

2,4-dichloro-7-(4-chlorophenyl)·6,7-dihydro-5 //-cyclopenta[d]pyrimidine (300 mg, 1.001 mmol), A solution of methylamine hydrochloride (135 mg, 2.003 mmol) and DIPEA (0.700 mL, 4.01 mm 〇i) in MeOH (6 mL) The solvent was removed in vacuo and the crude was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Pyrimidine-4-amine (101 mg, 0.343 mmol, yield 34.3%). LC-MS (M+H)

Preparation Q 2,4·Diqi-7-(3,4-difluorophenyl)-6,7-dihydro-5/ί-cyclopenta[d]pyrimidine 149653.doc •151 - 201107311

Cl

Intermediate Q(l) 7-(3,4-I It stupid)_6,7·Di-argon cyclopentazone 2 2,4(3/ί,5//)-dione

Stir 2_(3,4-difluorophenyl)cyclopentanone (prepared as intermediates P(1) and P(2)) at 58t: in South Valley Valley (1 5 g, 7 65 mmQi) and anisomeric groups A solution of formazan (1.129 g '1〇·70 mm〇1) for 1 hour. The temperature was raised to not and then (iv) the anti-complex for 2 hours. After cooling to room temperature, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the oily residue was purified by silica gel column chromatography to afford 7-(3,4-di-l-phenyl)-6,7-dihydrocyclopenta[e] as a white solid. [1,3]oxazine_ 2,4(3//,5//)--_(1.〇5 g, 3.96 mmol, yield 5i.gy0). H NMR (500 MHz, CDC13) δ ppm 8.16 (1H, br s), 7.15 (1H, dt, "7=10.0, 8.3 Hz), 6.97-7.05 (1H, m), 6.88-6.95 (1H, m) , 2.80-2.90 (1H, m), 2.61-2.78 (2H, m), 0.78-0.86 (2H, 149653.doc -152- 201107311 m). Intermediate Q(2) 7-(3,4-difluorophenyl)-6,7-dihydro-1open-cyclopenta[(1]pyrimidine_ 2,4(3i/,5/〇-二酉同

At 100 in a high pressure vessel (75 mL). (: 7_(3,4-difluorophenyl)_6,7-dihydrocyclopenta[e][i,3]oxazine-2,4(3 ugly,5//)-dione A solution of (1.05 g, 3.96 mmol) in EtOAc (EtOAc: EtOAc (EtOAc) 4-difluorophenyl)-6,7-dihydro-1H-cyclopenta[d]peptidyl-2,4(3i/,5/i)-dizinc (1.046 g, 3.96 mmol, produced Rate 100%). LC-MS (M+H)+ = 265.2.

Preparation Q 2,4-Dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-57/-cyclopenta[d]pyrimidine

7-(3,4-Difluorophenyl)-6,7-dihydro-/β-cyclopenta[d]pyrimidine-2,4 (3i/,5/f)-dione (500 mg, 1.892 mmol), POCl3 (5644 μί, 60.6 mmol) and iV, #-dimethylaniline (1931 pL, 15.14 mmol), 149653.doc -153· 201107311 The compound was heated at 120 ° C overnight. The reaction mixture was poured into a beaker containing ice. The inner wall of the reaction vessel was washed with DCM, and once the ice was completely melted, the contents of the beaker were placed in a separatory funnel. The organic layer was separated and the aqueous layer was extracted with D. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography to give 2,4-di-s--7-(3,4-difluorophenyl)·6,7-dihydro-5-cyclopentane And (4) pyrimidine (446 mg ' 1.481 mmo yield 78%). LC-MS (M+H)+ = 301.1. Preparation qa 2-gas-7-(3,4-difluorophenyl)_;\^-dimethyl-6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine

The 2,4-dioxa-7-(3,4-difluorophenyl)-6,7-dihydro-5//-cyclopenta[d] mouth was stirred at room temperature. A solution of 446 mg (1.481 mmol) in excess of diamine (2.222 mL, 4.44 mmol) in MeOH (6 mL) The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel column chromatography to give 2 gas _7_(3,4-difluorophenyl)·#,#_dimethyl_6,7-dihydrocyclohexane Pentopyrimidine·4_amine (146 mg '0.471 mmol' yield 31.8%). LC-MS (M+H)+ = 310.2. Preparation qb 2 -Chloro-7-(3,4-disorganophenyl)-iV·decyl-6,7-dihydro-5//-cyclopenta[&lt;^] decylamine 149653. Doc •154· 201107311

^NH

Stir 2,4-dioxa-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (421 mg, 1.398 mmol) at room temperature, A A solution of the amine hydrochloride (283 mg, 4.19 mmol) and DIPEA (1.465 mL, 8.39 mmol) in methanol (10 mL)! hour. The solvent was removed in vacuo and the crude was purified by EtOAc EtOAc EtOAc EtOAc EtOAc /-Cyclopenta[d]〇^ bite-4-amine (154 mg, 0.521 mmol, yield 37.2%). LC-MS (Μ+Η)+=296·2.

Preparation R 2,4-Dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidine

CI

Intermediate R(l) 1-cyclopentenyl-4-(trifluoromethoxy)benzeneky~\_/-〇cF3 gives (4-(trifluoromethoxy)phenyl) magnesium bromide in the middle The compound p(1) is reacted to give 1-cyclopentenyl-4-(trifluoromethoxy)benzene. 149653.doc •155· 201107311 Intermediate R(2) 2-(4-(trisethoxy)phenyl)cyclopentanone

1-cyclopentenyl-4-(trifluoromethoxy)benzene is reacted as an intermediate p(2) to give 2-(4-(trifluoromethoxy)phenyl)cyclopentanone. Intermediate R(3) 7-(4-(Difluoromethoxy)phenyl)-6,7-dihydrocyclopenta[e][i,3]^嘻_2 4 (3H,5H)- Diketone

2-(4-(Trifluoromethoxy)phenyl)cyclopentanone is reacted with the intermediate p(3) to give 7-(4-(trifluorodecyloxy)phenyl)-6,7 _ Dihydrocyclopentaoxazin-2,4(3H,5H)-dione. Intermediate R(4) 7-(4-(dioxamethoxy)carbyl)-6,7-dihydro-1-only-cyclopenta[4]. _ 2,4(3H,5H)·dione

149653.doc -156- 201107311 Let 7-(4-(trifluoromethoxy)phenyl)_6,7-dihydrocyclopentaoxazin-2,4(311,511)-dione as an intermediate? Reaction in the manner of (4) to give 7-(4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)- Dione.

Preparation R 2,4-dioxa-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

7-(4-(Trifluoromethoxy)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-2,4(3H,5H)-dione as a preparation p The reaction gave 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine as a pink solid. LC-MS (M+H)+ = 349.2. NMR (500 MHz, CD30D) δ ppm 7.31 (2H, dd, J = 2.0, 7.7 Hz), 7.25 (2H, d, J=1A Hz), 4.56 (1H, t, 7=8.8 Hz), 3.15 (1H , ddd, 7=3.8, 9.1, 16.9 Hz), 3.09-3.00 (1H, m), 2.81-2.72 (1H, m), 2.27-2.22 (lH, m). Preparation Ra 2-chloro-iV-methyl-7-(4-(trifluoromethoxy)phenyl)_6,7-dihydro-5//-cyclopenta[d]°f.定-4-amine 149653.doc -157· 201107311

Stir 2,4-dioxa-7-(4-(trifluorodecyloxy)phenyl)_6,7•two-rat-5-cyclopenta[d] mouth bite (2〇〇mg at room temperature) '0.573 mmol) and a solution of methylamine (0.286 mL '0.573 mmol) in MeOH (5 mL) The solvent was removed in vacuo to give crude 2-carbo-indolyl-7-(4-(trifluoromethoxy)phenyl)-6,7-monohydro-5i/-cyclopenta[d] Amine (220 mg, 0.640 mmol, yield 112%). LC-MS (Μ+Η)+=343·9. Preparation Rb 2-cyclohexyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5/f-cyclopenta[d]pyridin-4-amine

Stir 2,4-dioxa-7-(4-(trifluorodecyloxy)phenyl)_6,7_two wind-5//-1⁄4 penta[(1]°3⁄4 t» at room temperature (200 mg, 0.573 mmol) and a solution of ethylamine (0.286 mL, 0.573 mmol) in MeOH (2 mL). _气_#_ Ethyl-7-(4-(trifluoromethoxy)phenyl)_6,7-dihydro-5 ugly-cyclopenta[d]pyrimidin-4-amine (190 mg, 0.531 mmol , yield 93%). LC-MS (M+H)+= 149653.doc -158-201107311 358.2. Preparation Rc 2-Gas-4-(3,3-Difluoroazetidin% Butane Base) '7-(4-(tri-11methoxy)benzenehydro-5//-cyclopenta[d] squirt

Stir 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5/7-cyclopenta[d]pyrimidine (250 mg, 0.716) at room temperature Methyl), 3,3-difluoroazetidine hydrochloride (186 mg ' 1.432 mmol) and DIPEA (0.500 mL, 2.86 mmol) in MeOH (3 mL) The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography to afford 2···················· Oxymethoxyoxy)phenyl)_6,7-dihydro-5//-cyclopenta[d] deg. (244 mg, 0.601 mmol, yield 84%). LC-MS (M+H)+ = 406.0. Preparation Rd 2-Gas dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine

149653.doc -159- 201107311 Stirring 2,4-dioxa- 7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5仏cyclopenta[d]pyrimidine at ambient temperature (250 mg, 0.716 mmol) and a solution of diamine (0.716 mL, 1.432 mmol) in MeOH (2 mL) The solvent was removed in vacuo and the crude product was purified by column chromatography to give 2-chloro-# dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydrocyclopentane And [d] mouth bite 4-amine (250 mg, 0.699 mmol, yield 983⁄4). LC_MS (Μ+Η)+=358·0» Preparation Re 4·(azetidin-1·yl)-2- gas-7-(4-(trifluoromethoxy)phenyl)_6 , 7_ dihydro-5//-cyclopenta[d] mouth bite

Stir 2,4-dioxa-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine (250 mg, 0.716) at room temperature Methyl) and azetidin (82 mg ' 1.432 mmol) in MeOH (3 mL) The solvent was removed in vacuo and the crude product was purified by column chromatography to afford (azetidin-l-yl)-2-y-7-(4-(trifluoromethoxy)phenyl) -6,7-Dihydro-5//-cyclopenta[d]pyrimidine (238 mg, 0.644 mmol, yield 90%). LC-MS (M+H)+ = 371.2.

Preparation S 2,4-Dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine 149653.doc -160- 201107311

Cl

Intermediate S(l) (lS, 2R)-2-(3,5-difluorophenyl)cyclopentanol

F The flask was fed with (3,5-difluorophenyl)magnesium bromide (149 mL, 149 〇1) and copper iodide (1) (1·9 〇1 g, 9 98 〇1). To the reaction mixture was added dropwise 6-oxabicyclo[3.1.0]hexane (12.53 g, 149 mmol) dissolved in THF (25 mL). After the addition of the epoxide, the reaction mixture is warmed up. The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of a vaporized ammonium solution. Ethyl ether was added and the organic layer was collected, dried (Na2S?) and concentrated. The crude product was purified by silica gel column chromatography to give (1S,2R)-2-(3,5-difluorophenyl)cyclopentanol (26.5 g, 134 mmol, yield 90%) NMR ( 500 MHz, CDC13) δ ppm 6.72 (2H, dd, J=8.7, 2 〇Hz), 6.50-6.63 (1H, m), 2.97 (1H, br s), 2.78 (1H, d, J=i0&gt;1

Hz), 1.96-2.15 (2H, m), 1.66-1.85 (2H, m), 1.53-1.65 (2H m). Intermediate S(2) 2-(3,5-difluorophenyl)cyclopentanone 149653.doc •161 · 201107311

g ' 30.3 mmol) was added to a solution of Martin's high iodine (15.41 to (lS,2R)-2-(3,5-difluorophenyl)cyclopentanol (6 CH2C12 (150 mL)). The reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with dichloromethane and then evaporated and evaporated. The crude product was purified by hydrazine column chromatography to give 2-(3,5-difluorophenyl)cyclopentane (4 765 g, 24 29 mmo yield: 80 〇 /.) LC-MS (Μ+Η) )+=197·〇.iH NMR (5〇〇MHz, CDC13) δ ppm 6.70 (2H, d, J=6.7 Hz), 6.52-6.67 (1H, m), 3.17-3.33 (1H, m), 2.33 -2.56 (2H, m), 2.06-2.26 (2H, m), 2·01 (1H, dd, *7=11.7, 6.3 Hz), 1.89 (1H, br s) Intermediate S(3) 7- (3,5-difluorophenyl)_6,7-dihydrocyclopentaoxazine_

A mixture of 2-(3,5-fluorophenyl)cyclopentanone (4.765 g, 24.29 mmol) and isocyanoguanidine chloride (4.61 g '43.7 mmol) was heated at 58 ° C for 1 hour at 130 . (The next heating was carried out for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was separated 149653.doc •162·201107311 and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered and evaporated. Hydrogencyclopenta[6][1,3]ox. Qin-2,4(3dan,5dan)-dione (7〇〇mg, 2.64mmol, yield 〇87%). LC-MS ( Μ+Η) +=266·1.咕NMR (500 MHz, CDC13) δ ppm 8-79 (1H, br s), 6.68-6.86 (3H, m), 4.22 (1H, br s), 2.87 (1H , dt, "7=7.0, 4.4 Hz), 2.63-2.82 (2H, m), 2.15 (ih, br s). Intermediate S(4) 7-(3,5-fluoro-based)-6, 7-Dihydro-1 //-cyclopenta[d] sputum _ 2,4 (3 ugly, 5 open)-dione

7-(3,5-Difluorophenyl)-6,7-dihydrocyclopenta[],1,3]oxazine-2,4(3//,5 in a high pressure (350 mL) vessel /ί)-Dione (700 mg, 2.64 mmol) in EtOAc (50 mL, EtOAc) The reaction mixture was cooled and concentrated in vacuo to give crude 7-(3,5-difluorophenyl)-6,7-dihydro-1-cyclopenta[d]pyrimidine-2,4 (3), 5/ /) - _ (74 〇 mg, 2.80 mmol, yield 106%). LC-MS (Μ+Η)+=265·0. Preparation S 2,4-Dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5-open-cyclopenta[0]pyrimidine 149653.doc • 163· 201107311

7(3,5--Fluorophenyl)_6,7-dihydro-1 good-cyclopenta[&lt;^]1&gt; A solution of _2, 4 (3//, a class (740 mg' 2.8 〇mmo 丨) in phosphorus oxyphosphorus (7.691 mL, 84 mm.01) was heated in a microwave at 110 ° C for 1 hour. The mixture was poured into ice. Once the ice was melted, the product was extracted with dioxane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered, and the solvent was removed in vacuo and the residue was purified by chromatography. , 2,4_digas_7_(3,5-diphenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine (200 mg, 0.664 mmol, yield 23 72%) LC_ms (M+H)+=3〇1 〇 Preparation Sa 2-Chloro-7-(3,5-difluorophenyl)-sodium decyl-6,7-dihydrocyclopenta[d] Pyrimidine-4-amine

Mix 2,4 -diqi-7-(3,5-difluorophenyl)-6,7-dihydro-5//-cyclopenta[d] mouth bite (2〇〇) under the dish A solution of mg, 0.664 mmol) and decylamine (0.664 mL, 1.328 mmol) in EtOAc (3 mL) The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography to give 2-chloro-7-(3,5-diphenyl)·#-methyl-6,7-dihydro-5/ /-Cyclopenta[d]pyrimidin-4-amine (60 149653.doc • 164·201107311 mg, 0.203 mmol, yield 30.5%). LC-MS (Μ+Η)+=296·1. Preparation τ 2,4-Dichloro-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5i/-cyclopenta[d]pyrimidine

CI

Intermediate T(l) (lS, 2R)-2-(3,4,5-trifluorophenyl)cyclopentanol

F F To a suspension of magnesium (2.88 g, 118 mmol) in THF (110 mL) was slowly added &lt;RTI ID=0.0&gt;&gt; After the addition, the reaction mixture was heated under reflux for 2 hours. Copper molybdenum (1) (1.506 g, 7.91 mmol) and 6-oxabicyclo[3_1.0]hexane (9.93 g, 118 mmol) dissolved in THF (20 mL) were added dropwise to this reaction mixture. . After the addition of the epoxide, the reaction mixture is warmed up. The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of a vaporized ammonium solution. Ethyl scale was added and the organic layer was collected to dry (NajO4) and concentrated. The crude product was purified by silica gel column chromatography to afford (l,,,,,,,,,,,,,,,,,,,,,,,,, JH NMR (500 MHz, CDC13) δ ppm 6.79-7.02 (2Η, m), 4.10- 4.21 (1H, m), 2.75-2.91 (1H, m), 2.08-2.24 (2H, m), 1.75- 149653. Doc -165- 201107311 1.93 (2H,m), 1.50-1.75 (2H,m). Intermediate T(2) 2-(3,4,5-trifluorophenyl)cyclopentanone

, -&amp; 丨 丨 仟 仟 愿 &̄; Dilute the reaction with dioxane and add by! N Na〇H to quench. The organic layer was collected, dried (Na2S 4) and concentrated. The crude product was purified by hydrazine column chromatography to give 2-(3,4,5-trifluorophenyl)cyclopentanone (31 </ RTI> </ RTI> <RTIgt; LC-MS (M+H)+ = 2 15.1. Intermediate T(3) 7-(3,4,5-trifluorophenyl)_6,7-dihydrocyclopenta[][1,3]oxazine_ 2,4(3//,5// )-dione

A mixture of 2-(3,4,5-trisylphenyl)cyclopentanone (2 g, 9.34 mmol.) and isocyanomethoxy (1.773 g, 16.81 mmol) was heated at 58 °C. The reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate. The machine layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography to give 7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][l,3] Oxazine-2,4(3/ί,5//)-dione (1.227 g, 4.33 mm 〇i, yield 46.4%) 〇LC-MS (M+H)+=284. Intermediate T(4) 7-(3,4,5-di-phenylphenyl)-6,7-dihydro-1/f-cyclopenta[d]biting _ 2,4(3//,5 //)-dione

7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4 (3 ugly) in a high pressure (350 mL) vessel A solution of the diketone (1.23 g, 4.34 mmol) in concentrated ammonium hydroxide (75 mL, 1926 mmol) was taken at 100. Heat under the armpits overnight. The reaction mixture was cooled and concentrated in vacuo to give crude <RTI ID=0.0>-(3,4,5-trifluorophenyl)-6,7-dihydro-1//-cyclopenta[d]pyrimidine-2,4 (3/ /, 5 / /) • diketone (1.3 g, 4.61 mmol, yield 106%). LC-MS (Μ+Η)+=283·0. Preparation τ 2,4-dioxa-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5/f-cyclopenta[d]pyrimidine

• 167- 149653.doc 201107311 7-(3,4,5-trisphenyl)-6,7-dihydro-1//-cyclopenta[d] d close bit _ 2,4(3/ A solution of /, 5//)-dione (1.3 g ' 4.61 mmol) in phosphorus oxyhydroxide (5 mL, 54.6 mmol) was heated in a microwave at 110 ° C for 1 hour. This reaction was repeated with an additional 8 mg of starting material. The reaction mixture was poured into ice and combined. Once the ice melts, the product is extracted with digas methane. The combined organic extracts were dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Dhenyl)-6,7·dihydro-5//-cyclopenta[d]pyrimidine (498 mg, 1.561 mm 〇l, yield 33.9%). LC-MS (M+H)+ = 318.9. Preparation Τα 2-Gas-ΛΓ-Mercapto-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5 ft-cyclopenta[d]. dense. 4-amine

XNH

Stir 2,4-dichloro-7-(3,4,5-trifluorophenyl)_6,7-dihydro-5 open-cyclopenta[d]pyrimidine (498 mg' 1.561 mmol) at room temperature A solution of methylamine (1.561 mL, 3-12 mmol) in MeOH (1 mL) was taken for 1 hour. The reaction was observed to be incomplete. Additional portions of methylamine (1.561 mL·, 3·12 mmo丨) were added to the reaction mixture until the end of the reaction. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography to afford 2-dichloro-7-(3,5-difluorophenyl)_#_methyl_6,7-monohydro-57/- Cyclopenta[d]pyrimidinamine (60 mg, 0.203 mmo 149653.doc 201107311 rate 30.5%). LC-MS (M+H)+ = 314.0. Preparation Tb 2-Gas-4-(3,3-difluoropyridin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5// -cyclopenta[d]pyrimidine

Stir 2,4-dioxa-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5孖-cyclopenta[d]pyrimidine (1 〇〇 mg, at room temperature 0.313 mmol), DIPEA (0.066 mL, 0.376 mmol) and 3,3-difluoropyrrolidine hydrochloride (45.0 mg, 0.313)

A solution of mmol) for 1 hour. The solvent was removed in vacuo and the residue was purified by column chromatography to afford 2-[sup. Difluoro 1 benzyl) _6,7-diaza-5//-cycloindole [(1]11 mil. (1〇5 111§, 0.269 mmo yield 86%). LC-MS (M+ H) + = 390.0. Preparation Tc 2-chloro-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-

6,7-dihydro-5//-cyclopenta[d]pyrimidine N

149653.doc -169- 201107311

To purify the residue. The solvent was removed in vacuo, and 2-[3,3-difluoroazetidinyl-l-yl)_7_ (3,4,5-tri-phenyl) was obtained by column chromatography. · 6,7_Dinitrogen_5 is good for ring and (4) mouth bite (1〇5, 0.279 mmol, yield 89%). lC_MS (Μ+Η)+=376 〇. Preparation υ 2,4-diqi-7-(2,4-difluorophenyl)r6,7-dihydro_5 ugly-cyclopenta[d]pyrimidine

Intermediate UU) cyclopentenyl-2,4-difluorobenzene

To a solution of 0.497 Μ(2,4-difluorophenyl)magnesium bromide in THF (32.4 g s 149 mmol) was carefully added cyclopentanone (13.23 mL, 149 mmol). At the end of the addition, the reaction mixture was heated under reflux for 2 hours. Ice (10 g) and 6 N aqueous hydrochloric acid were added. The reaction mixture was extracted with diethyl ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered over 149 353. The solvent was removed in vacuo and the residue was purified by chromatography eluting eluting eluting eluting eluting eluting ). LC-MS (M+H)+ = 181.0. Towel NMR (500 MHz, CDC13) δ ppm 7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H, m), 2.51-2.58 ( 2H, m), 1.93-2.02 (2H, m). Intermediate U(2)

2-(2,4-difluorophenyl)cyclopentanone

F A mixture of 90% decanoic acid (26.4 mL, 689 mmol) and 30% hydrogen peroxide (6 〇 mL, 39.2 mmol) was warmed at 4 ° C for 1 Torr. The resulting solution was carefully added to the cyclopentenyl 2,4-difluoro stupid (7 〇 64 g, 39.2 mmol) under stirring. The two phase system was initially stirred at room temperature. After a period of time, a self-heating reaction occurred and the temperature rose to about 5 〇. Hey. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the careful addition of saturated sodium bicarbonate solution. Add ether and vigorously shake the contents of the separatory funnel. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo, and the residue was purified by chromatography eluting to afford to afford to give the product as a colorless oil.

Base)% pentanone (3.503 g '1 7.8 5 mmol, yield 45.5%). LC-MS (M+H)+=195.2 NMR (500 MHz, CDC13) δ ppm 7.08 (1H, td, /=8.4, 6.4 Hz), 6.76-6.86 (2H, m), 3.42 (1H, dd H9653 .doc • 171 - 201107311 /=12.2, 8.9 Hz), 2.42-2.53 (2H, m), 2.28-2.39 (1H, m), 2.13-2.23 (1H, m), 1.86-2.10 (2H, m). The intermediate U(3) 7-(2,4-·one gas base)_6,7-_ is a gas and [e][i,3]. Called · 2,4(3//,5//)-dione

a mixture of 2-(2,4-difluorophenyl)cyclopentanone (1_014 layer, 5.17 111111〇1) and 50 wt/〇isocyanoindole chlorobenzene (1.963 g, 9.30 mmol) - heating at 58 ° C for 1 hour and heating at 120 ° C for 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with aqueous sodium hydrogen sulfate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluted eluted elut elut elut , 3]oxazine-2,4(3//,5/〇-dione (499.3 1^, 1.883 mmol' yield 36.4%). LC-MS (Μ+Η)+=266·2. NMR ( 500 MHz, CDC13) δ ppm 8.19-8.64 (1H, m), 7.10 (1H, td, 7=8.5, 6.3 Hz), 6.78-6.92 (2H, m), 4.36-4.49 (1H, m), 2.79- 2.92 (1H, m), 2.59-2.78 (2H, m), 2.08 (1H, ddd, J=9.3, 6.9, 6.7 Hz). Intermediate U(4) 7-(2,4-difluorophenyl) -6,7-dihydro-17/-cyclopenta[(1]pyrimidine- 149653.doc -172- 201107311 2,4(3/ί,5//)-dione

2-(2,4-difluorophenyl)cyclopentanone (1_014 g, 5 17 mm〇i) and 5 〇wt% isocyanoindole as a stupid solution (1 963 g, 9 3 〇mm The mixed Φ of 〇i) was heated at 5 8 C for 1 hour and heated at 120 ° C for 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with aqueous sodium hydrogen sulfate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography to afford 7-(2,4-difluorophenyl)-6,7-dihydrocyclopentane as a brown solid. [1,3]oxazine-2,4(3,5//)-dione (499.3 11^, 1.83 mmo yield: 36.4%). LC-MS (Μ+Η)+=265·1. Preparation υ # 2,4-diqi-7-(2,4-difluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine

7-Phenyl-6,7-dihydro-1//-cyclopenta[d]pyrimidine-2,4(3//,5//)-dione (248.5 mg, 0.940 mmol) in three gases The solution in oxyphosphorus (1 〇 niL) was heated in a microwave at 130 ° C for 2 hours. The reaction mixture was poured into an ice-containing beaker 149653.doc .173-201107311. - Once the ice melts, it is used immediately: the gas is burned to extract the product. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluted eluted eluted eluted eluted eluted [d]pyrimidine (267.9 mg, 95%). LC-MS (M+H)+ = 30l. Preparation υα 2-chloro-7-(2,4-fluorophenyl)_#_mercapto-6,7-dihydro-5 tablets cyclopenta[d]pyrimidin-4-amine

To 2,4-dioxa-7-(2,4-difluorophenyl)-6,7-diargon-5//-cyclopenta[d]pyrimidine (267.9 mg, 0.890 mmol) in decyl alcohol ( A solution of 2 guanamine in methanol (0.890 mL, 1.779 mmol) was added to the solution in 5 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluting elut elut elut elut Dihydro-5 oxime-cyclopenta[d]pyrimidin-4-amine (184.6 mg, 0.624 mmol, yield 70.2%). LC-MS (Μ+Η)+=296·1.

Preparation V 2,4-dioxa-7-mercapto-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine 149653.doc -174- 201107311

Cl

Intermediate v(l) 2-methyl-2-phenylcyclopentanone

Add 2_phenylcyclopentanone (5 〇〇 mg, 3.12 mmol) to DME (3571 μM) in a slurry of 60% &gt;JaH (125 mg, 3.12 mmol) at 〇C. Mel (898 μί, 14.36 mmol) was added, and the solution was heated to reflux for 2 hours. The reaction was poured onto ice and extracted 3 times with EtOAc. The organic extracts were washed with brine and dried over MgSO. Filtration and concentration in vacuo, applied to silica gel and dissolved in a solution to give 2-methyl-2-phenylcyclopentanone (4〇1 7 , 2 3〇5 〇1, yield 73.9%) 〇LC-MS (M+H)+=175.1 〇]H NMR (500 MHz, CDC13) δ ppm 7.29-7.37 (4 H, m), 7.20-7.24 (1 H, m), 2.54 (1 H, dt, ^-12.51 , 6.26 Hz), 2.34 (2 H, t, 7=7.63 Hz), 1.82-2.05 (3 H, m), 1.38 (3 H, s) Intermediate V(2) 7-mercapto-7-benzene Base-6,7_dihydrocyclopenta[e][1,3]ming 嗓_2,4(3h,5h)-dione 149653.doc •175· 201107311

Combine 2-mercapto-2-phenylcyclopentanone (intermediate v(l)) (705.5 mg, 4.05 mmol) with isocyanoguanidine chloride (1700 mg, 8.06 mmol), rinse with hydrazine, and seal with Seal the tube. At 58. (: heating under 1 hour, followed by heating at 130 C for 1.75 hours. Cooling to room temperature. The tube was carefully opened (hci), and the residue was taken from EtOAc. The combined organic layers were washed with brine <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> - dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (yield 43%). LC-MS (M+H)+= 244.1 〇'H NMR (500 MHz, CDC13) δ ppm 8.12 (1 H, br. s.), 7.32-7.38 (2 H, m), 7.26-7.30 (3 H, m), 2.69-2.75 (2 H, m), 2.43 -2.52 (1 H, m), 2.21-2.29 (1 H, m), 1.68 (3 H, s) Intermediate V(3) 7-Methyl-7-phenyl-6,7-dihydro- 1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione

Solid 7-mercapto-7-phenyl-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4(3H,5H)-dione (420 mg) in a sealed tube , 1.727 mmol) Zhongtian 149653.doc • 176· 201107311 Enriched hydrogen hydroxide (4706 pL, 121 mmol). The tube was heated at 80 ° C for 4 hours. Cool to room temperature. The solvent was removed under a stream of N2. The residue was loaded onto silica gel and eluted with EtOAc / hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydro-1 s-cyclopenta[d]pyrimidine-2,4 (3, 5Η)-dione (293 mg, 1.209 mmol, yield 70.0%). LC-MS (M+H)+ = 243.1.

Preparation V 2,4-diqi-7-mercapto-7-phenyl-6,7-dihydro-5H-cycloindole[d] bite

CI

Dissolve 7-methyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d], _2,4 (3H,5H)-dione (48.2 mg, 0.199 mmol) P〇Cl3 (742 μί, 7.96 mmol) was placed in a microwave vial. The reaction was heated in a microwave for 1 hour at i2 °C. Cool to room temperature and pour into ice. Once the ice melted, it was extracted 3 times with EtOAc. Dry <RTIgt; Rapid passage through the EtOAc/Hex SG column gave 2,4-dichloro-7-mercapto-7-phenyl-6,7-dihydro-5H-cycloindolo[d]pyrimidine (43.1 mg, 0.154 mmol) , yield 78%). LC-MS (M+H)+ = 279.1. Preparation Va 2-chloro-N-ethyl-7-mercapto-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine.定-4 -amine 149653.doc •177· 201107311

NH

2,4-Dichloro-7-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d] mouth bit (preparation ν) (43·1 mg, at room temperature, 0.154 mmol) A solution of 2 Μethylamine (3 86 μΐ '0·772 mmol) diluted with 390 pL MeOH was added to a solution of THF (772 μ!) (the total reactant was in 1:i THF/MeOH. 1)). Dissolve at the temperature. Remove the solvent and subject the residue to a ruthenium tube column using EtEAc/Hex gradient to give 2-gas-N-ethyl-7-methyl-7-phenyl. -6,7-Two winds 5H cyclopenta[d] mouth bite _4_amine (38.0 mg, 0.132 mmol, yield 86%) °

Preparation W 2,4-digas_7·allyl·7_phenyl_6,7-dihydro-5H•cyclopenta[d]pyrimidine

CI

Intermediate W(l) 2-allyl-2-phenylcyclopentanone

Using the shoe y. m ^ ^ procedure of the intermediate 乂 (1), allyl bromide was obtained using allyl bromide. 149653.doc -178· 201107311 Intermediate W(2) 7-allyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H, 5H)-dione

Using the method of the intermediate V(2), 7-allyl-7-phenyl-6,7-dihydrocyclopenta[e][l,3]oxazine-2,4(3H,5H) was obtained. - Diketone. !H NMR (500 MHz, CDCi3) δ ppm 8.06 (1 Η, br. s.), 7.23-7.43 (5 H, m), 5.59-5.72 (1 H, m, 7=17.09, 9.99, 7.21, 7.21 Hz), 5.08-5.23 (2 H, m), 2.73-2.87 (2 H, m), 2.63-2.71 (2 H, m), 2.38-2.49 (2 H, m). Intermediate W(3) 7-Dilyl-7-phenyl-6,7-diaza-1H-cycloindole [d]. -2,4(3H,5H)-dione

Using the method of intermediate V(3), 7-allyl-7-phenyl-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione was obtained. . LC-MS (M+H)+ = 269.1.

Preparation W 2,4 -diqi-7-dipropyl-7-phenyl-6,7-diox-5 H-cycloindole [d] ° bite 149653.doc 179- 201107311

The method of Preparation v was used to obtain 2,4-dichloro-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine. LC-MS (M+H)+ = 305.0. Preparation Wa 2-gas-N-ethyl-7-allyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine_4_amine

Using the procedure of Preparation Va', 2-gas·indole-ethyl-7-allyl-7-phenyldihydro-5Η-cyclopenta[d]pyrimidin-4-amine was obtained. LC-MS (Μ+Η)+= 314.1.

Preparation X 2,4-Dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5-pyrido[4,3-d] stilbene

Intermediate X(l) 149653.doc -180- 201107311 3_Iodine·4,4-dimethoxytetrahydro-2H-pyran

Ment) with dihydro-2H_pyranose - a mixture of trimethoxynonane (82 mL, 745 4 (3H)-one (14.92 g, 149 mmol) was cooled to 4 ° C. Diiodine) (37.8 g, 149 mmol) and maintaining the temperature between ye and 5 ° C. The reaction mixture was stirred for 1 min. The cooling bath was removed and stirred at 28 C for 10 min. The mixture was cooled to 丨〇〇c The mixture was stirred for 1 hour, then stirred at room temperature for 1 hour. The reaction mixture was diluted with CH.sub.2 and cooled in ice water. The mixture was slowly quenched with saturated Nad2.3. The mixture was separated. The aqueous layer was extracted with CH2CI2. The organic layer was dried over Na 2 EtOAc (EtOAc m.). M, yield 82%) NMR (500 • MHz, CDC13) δ ppm 4.24 (1 Hs t, J=2.29 Hz), 3.93-4.02 (1 H, m), 3.83-3.92 (2 H, m), 3.55 (1 H, d, J=2.44 Hz), 3.24 (3 H, s), 3.20 (3 H, s), 2.33 (1 H, dd, J=4.88, 2.14 Hz), 1.79 (1 H, dd , J=14.34, 2.44 Hz) ° Intermediate X(2) 3-(3,5-monofluorophenyl)dihydro-21^-&lt; 1 bottom _4 (3)-ketone

149653.doc -181 - 201107311 (1 ft, 2 ft) 2-aminocyclohexanol hydrochloride (〇.418 g, 2.76 mmol), chlorine hexahydrate under &lt;^2 under 10 °〇 A mixture of nickel (11) (0.328 g, 1.378 mmol) and 3,5-difluorophenyl decanoic acid (6.53 g, 41·3 mmol) was added dropwise a solution of NaHMDS in THF (55.1 mL, 55.1 mmol). After the addition, the mixture was stirred at 10 ° C for 20 minutes. 2-propanol (113 mL) was added at 〇 ° C (previously bubbling with N 2 ), then the mixture was stirred at room temperature for 1 hr. 3-Moth-4,4-dimethoxytetrahydro-2H-pyran (preparative hydrazine) (7.5 g, 27.6 mmol) in THF solution was added dropwise and at 60. (The mixture was heated overnight. The reaction mixture was cooled in EtOAc EtOAc EtOAc (EtOAc) The residue was purified by column chromatography to give 3-(3,5-difluorophenyl)dihydro-2H-pyran-4(3H)-one (1.6 g, 7.54 mm, yield: 27.4%). NMR (500 MHz, CDC13) δ ppm 6.78 (dd, 1 = 8.24, 2.14 Hz, 2 H) 6.62-6.75 (m, 1 H) 4.21 (dd, J-ll.44, 5.65 Hz, 2 H) 3.85- 4.01 (m, 2 H) 3.76 (dd, J=8.55, 6·10 Hz, 1 H) 2.60-2.75 (m, 1 H) 2.48-2.60 (m, 1 H) Intermediate X(3) 8- (3,5-difluorophenyl)_7,8-dihydrofuro[3,4_6][1,3]1&gt;oxazine-2,4(3H,5H)-dione

3-(3,5-Difluorophenyl)dihydro-2H-pyran-4(3H)-_ 149653.doc •182· 201107311 in a sealed vial

A mixture of (Preparation X2) (800 mg, 3.77 mmol) and isocyano helium (557 mg ' 5.28 mmol) was heated at 55 ° C for 1 hour, followed by heating at 130 ° C for 2 hours. The mixture was cooled to room temperature. It was partitioned between EtOAc and sat. NaHC.sub.3 solution. Extract with EtOAc (3 times). The combined organic layers were washed with brine, dried over Naz. The crude product was purified by hydrazine column chromatography to give 8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][l,3]°. -2,4(3H,5H)-dioxin (230 mg '0.818 mmol, yield 21.69%). LC-MS (M+H)+=282.0. 4 NMR (500 MHz, CDC13) δ ppm 8.94 (br, s., 1 H) 6.85-7.01 (m, 2 H) 6.81 (tt, J=8.81, 2.17 Hz, 1 H) 4.70 (d, J=15.56 Hz, 1 H) 4.49 (dd, J=15.56, 2.14 Hz, 1 H) 4.03-4.12 (m, 2 H) 3.68 (br. s.5 1 H) . Intermediate X(4) 8-(3,5-di-phenyl)-7,8-dihydro-111-11 bottom Nanhe[4,3-(1]11-bite-2,4(3H ,5H)-dione

8-(3,5-Difluorophenyl)-7,8-dihydropyrano[3,4-e][l,3]oxazine-2,4(3H,5H) in a sealed vial A mixture of diketone (preparative X3) (230 mg, 0.818 mmol) and ammonium hydroxide (2229 μ::, 57.3 mmol) was heated at 80 ° C for 4 hours. N2 was bubbled overnight to give 8-(3,5-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)- Ketone (191 mg, 0.682 149653.doc •183· 201107311

Mmo1 ' yield 83%), used as received. LC-MS (Μ+Η)+=281·1. Preparation X 2,4-mono-(3-(3,5-difluorophenyl)-7,8-diar-5-indole-[4,3-d]pyrimidine

8-(3,5-Difluorophenyl)_7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione in a microwave vial ( A mixture of the intermediate x(4)) (191 mg, 〇 682 mmol) and P 〇 C13 (1906 ι, 20.45 mmol) was heated in a microwave oven at 1 Torr for 2.5 hours. The mixture was poured onto ice, which was extracted with EtOAc (3 times) as soon as ice was melted, washed with brine, dried over Na 2 EtOAc and concentrated. The crude product was purified by hydrazine column chromatography to give 2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H- succinyl[4,3-d Mouth bite (117 mg, 0.369 mmol, yield 54.1%). LC-MS (Μ+Η) + = 317.1 〇&gt;Η NMR (400 MHz, CDC13) δ ppm 6.66-6.91 (m,3 H) 4.87-5.01 (m, ih) 4.70-4.83 (m,1 H) 4.13-4.27 (m, 2 H) 4.10 (t, J=4.03 Hz, 1 H). Preparation Xa 2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyridin-4-amine 149653 .doc -184- 201107311

Stir ethylamine (406 μί, 0.812 mmol), 2,4-dioxa-8-(3,5-difluorophenyl)-7,8-dihydro-511-pyrano[4, at room temperature. A mixture of 3-pyrimidine (preparative X) (117 mg, 0.369 mmol) and DIEA (161 μί, 0.922 mmol) in THF (1 845 pL) for 2 hr. The mixture was concentrated and purified by silica gel column chromatography to give 2-[3-(3,5-difluorophenyl)·v_6-yl-7,8-dihydro-5[pi]-pyrano[4. , 3-d]pyrimidin-4-amine (1〇4 mg, 〇319 mmol, yield 87%). LC-MS (Μ+Η)+=326·1. Preparation Υ il phenyl)-7,8-dihydro-5H-nivine. Bite Cl

2,4-digas-8-(3,4-intermediate Υ(2) 3-(3,4-difluorophenyl)dihydro-211-pyran-4(311)-_

FF 149653.doc •185- 201107311 3,4-difluorophenyl S-p-acid and 3-branched-4,4-dimethoxytetrahydro-2H-piperazine (intermediate X(l)) as in the middle The reaction is carried out as described in the compound X (2) to give 3-(3,4-difluorophenyl)dihydro-2H-0- s- s- 4-(3H)- s (the intermediate γ (2)). 'Η NMR (500 MHz, CDC13) 5 ppm 7.03-7.22 (m, 2 H) 6.95 (ddd, J=6.33, 4.20, 1.98 Hz, 1 H) 4.17-4.32 (m, 2 H) 3.96 (ddd, J =11.52, 9.84, 3.97 Hz, 1 H) 3.91 (dd, J=11.44, 9.00

Hz, 1 H) 3.77 (dd, J=8.85, 5.80 Hz, 1 H) 2.63-2.76 (m, 1 H) 2.49-2.62 (m, 1 H). Intermediate Y(3) 8-(3,4-mono-phenyl)-7,8-dihydro"[2,4-e][i,3]^t^- 2,4(3H ,5H)-dione

Let 3-(3,4-one-p-phenyl) digas-2H-pie. South-4(3H)-_|(intermediate γ(2)) reacts with isocyanurethane gas as described in the intermediate Χ(3) to give 8-(3,4·difluorophenyl) -7,8-Dihydropyrano[3,4-e][l,3]oxazine-2,4(3H,5H)-dione (intermediate γ(3)). LC-MS (Μ+Η)+=282·1. NMR (500 MHz, CDC13) δ ppm 7.08-7.20 (m, 3 H) 4.67 (d, J = 15.26 Hz, 1 H) 4.46 (dd, J = 15.56, 2.14 Hz, 1 H) 3.98-4.10 (m, 2 H) 3.67 (br. s., 1H). Intermediate Y(4) 149653.doc -186· 201107311 8-(3,4-Fluorophenyl)_7,8-dihydro-1H-pyrano[4,3 d]pyrimidine _ 2,4(3H, 5H)-dione οΰθ

F makes 8_(3,4_monophenyl)-7,8-dihydropyrano[3,4&lt;][1,3]&quot;oxazin-2,4(3H,5H)-anthracene The intermediate γ(7)) reacts with the hydrazine as described in the intermediate χ(4) to give 8_(3,4-difluorophenyl)-7,8-dihydro-1-indole_pipeno[4'3- d] mouth bite - 2, 4 (3 Η, 5 Η) - _ (intermediate γ (4)). LC_MS (Μ_ Η)+=279.1. Preparation Υ 2,4_monochloro _8_(3,4-difluorophenyl)·7,8-dihydro-5H-pyrano[4,3-d] D

2,4-Dichloro-8·(3,4-difluorophenyl)_7,8-dihydro·5H_pyrano[4,3 d]pyrimidine (intermediate Y(4)) and POCI3 The reaction was carried out as described in Preparation X to give 2'4- gas-8-(3,4-difluorophenyl)-7,8-dihydro-511-0. Nanhe [4,3-d] sound bite (preparation Y). LC-MS (M+H)+ = 317.1. Preparation Ya 149653.doc •187· 201107311 2-Gas-8-(3,4-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d Cancer 11-1,4-amine

2'4-Dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-piperidin (preparation Y) with ethylamine as in Preparation Xa The reaction is carried out to obtain 2_gas_8-(3,4-difluorophenyl)-indole·ethyl-7,8-dihydro-5H-pyrano[4,3 d] ringing-4-amine ( Preparation Ya) e [e-MS (Μ+Η)+=326·1. Preparation Yb gas_4-(3,3-difluoroazetidinyl small)_8_(3,4-difluorophenyl)-7,8-dihydro-5Η-pyrano[4,3_d Pyrimidine

Reacting 2,4-digas _8-(3,4-difluoro phenyl group &amp; «(preparation Y) with 3,3·digas I·, —mW[4,3-d] To obtain 2_J heterocyclic butyl sulphate as prepared in product Xa... benzene benzene... two gas: 3 · diaza nitrogen heterocyclic oxime [4,3-* (preparation 149653.doc ' 188- 201107311

Yb). LC.MS (M+H)+ = 374.1. Preparation Yc 2-Ga-8-(3,4-difluorophenyl)_N_methyl-7,8-dihydro·5H_pyrano[4,3_d]pyrimidin-4-amine

Making 2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3_d] cancer bite (preparation Y) with guanamine as preparation The reaction is carried out as described in Xa to give 2-ox-8-(3,4-difluorophenyl)_ν·methyl-7,8-dihydro-5H-pyrano[4,3-d] ° Bite _4_amine (preparation Yc). LC-MS (M+H)+=3 12.3. Preparation Z. 2,4_digas_8~(4_(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

Intermediate Z(2) 3-(4-(difluoroindolyl)phenyl)dihydro-2H-pyran-4(3H)-one 149653.doc •189· 201107311

4-(Trifluoromethyl)phenyl phthalic acid and 3-iodo-4,4-dimethoxytetrahydro-2H_pyran (intermediate X(l)) as described in intermediate X(2) The reaction took place to give 3_(4_(dioxamethyl)phenyl)dihydro-2H-0-pyran-4(3H)-one (intermediate z(2)). !H NMR (500 MHz, CDC13) δ ppm 7.61 (m, J=8.24 Hz, 2 H) 7.37 (m, J=7.93 Hz, 2 H) 4.26 (dd, J=11.44, 5.95 Hz, 2 H) 3.93 -4.05 (m, 2 H) 3.82-3.93 (m, 1 H) 2.64-2.81 (m, 1 H) 2.49-2.64 (m, 1 H) = intermediate Z(3) 8-(4-(trifluoro) Mercapto)phenyl)-7,8-dihydropyrano[3,4-e][l,3]histazine_ 2,4(3H,5H)-dione

3-(4-(Trifluoromethyl)phenyl)dihydro-2H-pyran-4(3H)-one (intermediate Z(2)) with isocyanohydrazine such as intermediate hydrazine (3) The reaction takes place in the above to give 8-(4-(trifluoromethyl)phenyl)-7,8-dihydropyrano[3,4^][1,3]oxoxime _ 2,4 (3Η , 5Η)-dione (intermediate ζ (3)). 'Η NMR (500 MHz, CDC13) δ ppm 9.47 (br. s., 1 H) 7.58. 7.75 (m, 2 H) 7.42-7.55 (m, 2 H) 4.68 (d, J = 15.56 Hz, 1 h 4.42-4.57 (m,1 H) 4.03-4.22 (m,2 H) 3.79 (br·s.,1 H). 149653.doc -190· 201107311 Intermediate Z(4) 8-(4-(Difluoromethyl)phenyl)_7,8-Dihydro_1H_pyrano[4,3 d]pyrimidine _ 2,4 (3H,5H)-dione oxime 4〇cf3 makes 8-(4-(trihydromethyl)phenyl)-7,8-dihydropyrano[3,4_e](1)3]azine-2,4 (3H,5H)-dione (intermediate z(3)) reacts with ammonium hydroxide as described in the intermediate χ(4) to give 8_(4-(trifluoromethyl)phenyl)-7,8 _ Dihydro _lH_ slightly. Nanhe [4,3-d; l bleed · 2, 4 (3 Η, 5 Η) _: ketone (intermediate ζ (4)). Lc ms (Μ-Η)+=313·1. The preparation Ζ 2,4-monox-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5Η-pipero[4,3·d]D is dense. set

CI

8-(4-(Tris-methyl)phenyl)7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-: _ (intermediate z ( 4)) reacting with p〇cl3 as described in the preparation of hydrazine to obtain 2,4_dioxa-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5-indole M-[4,3-d]pyrimidine (preparative preparation). LC_MS (elbow + printing ^ 349). 149653.doc -191- 201107311 Preparation Za 2-chloro-N-ethyl_8·(4_(trifluoromethyl)phenyl)_7,8-dihydro-5h_ Piperazo[4,3-d]pyrimidin-4-amine

CI

吏 'Chloro 8~(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-Bucky[4,3'd] mouth bit (preparation Z) with ethylamine as preparation The reaction was carried out as described in Xa, and was added to 2-gas_team ethyl_8_(4_(triponyl)phenyl)7,8-dihydro-5Η·uninan[4,3d]pyrimidine. Fixed ‘amine (preparation Za). Lc_ms (μ+Η)+= 358.1 制备 Preparation Zb 2 gas-N-mercapto-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyran

[4,3-d] spray α-1,4-amine

'ΝΗ CI

2,4·1 gas-8_(4_(difluoromethyl)phenyl)-7,8-dichloroπ·piperazino[4,3-d]pyrimidine (preparative oxime) with methylamine such as preparation Xa The reaction occurred in the above to obtain 2-gas-N-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H_149653.doc-192·201107311 0 4,3-d]pyrimidine-4-amine (preparative zb). LC-MS (M+H)+= 344.1 ° Preparation 2c 2-V-N-((R)-1-cyclopropylethyl)_8_(4-(trifluoromethyl)phenyl)-7,8_ Dihydro-5H-n-deoxy[4,3-d] spur-4-amine

Cf3 gives 2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-(1]pyrimidine (preparation 2) with (R)-1 -cyclopropylethylamine hydrochloride reacts as described in Preparation Xa to give 2-hydroxycyclopropylethyl)-8-(4-(difluoroindolyl)phenyl)-7,8 -Dihydro-5H-piperac[4,3-d]pyrimidin-4-amine (Preparation Zc). LC-MS (M+H)+ = 398.2. Preparation AAa 4-(2-Ga-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl)

CN 149653.doc -193· 201107311 Intermediate AA(2) 4-(4-Sideoxytetrahydro-2H-n-endan-3-yl)benzonitrile

Reaction of 4-cyanophenyl S-p-acid with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (intermediate X(l)) as described in intermediate X(2) 4_(4_Sideoxytetrahydro-; 2H-pyran-3-yl)benzonitrile (intermediate aa(2)) was obtained. LC-MS (M+H)+=202.1 〇'Η NMR (500 MHz, CDC13) δ ppm 7.66 (d, J=8.24 Hz, 2 H) 7.38 (d, J=8.55 Hz, 2 H) 4.23-4.31 (m, 2 H) 3.94-4.02 (m, 2 H) 3.85-3.92 (m, 1 H) 2.55-2.65 (m, 1 H) 2.52 (t, J=5.80 Hz, 1 H) ° Intermediate AA ( 3) 4-(2,4-di-oxy-2,3,4,5,7,8-hexahydropyrano[3,4_e][i,3]oxazin-8-yl)phenylhydrazine Nitrile

The 4-(4-oxo-tetrahydro-2H-piperidin-3-yl)benzonitrile (intermediate AA(2)) is reacted with isocyanoguanidine as described in the intermediate X(3) The reaction gives 4-(2,4-di-oxy-2,3,4,5,7,8-hexahydropyrano[3,4-e][l,3]oxazin-8-yl) Benzoonitrile (intermediate AA (3)). LC-MS (M+H)+ = 271.1. NMR (400 MHz, CDC13) δ ppm 7.57-7.78 (m, 2 H) 7.41- 149653.doc •194· 201107311 7.51 (m, 2 Η) 4.61-4.75 (m, 1 Η) 4.50 (dd, J=15.49 , 2.14

Hz, 1 H) 4.04-4.20 (m, 2 H) 3,78 (br. s" 1 H). Intermediate AA(4) 4-(2,4-one-oxy-2,3,4, 5,7,8-hexahydro-111-'1 bottom 啥[4,3_(}] 啸 -8-8-yl)benzonitrile

CN 4-(2,4-di-oxy-2,3,4,5,7,8-hexahydropiperazo[3,4-e][l,3]oxazin-8-yl) The benzonitrile (intermediate AA(3)) reacts with ammonium hydroxide as described in the intermediate hydrazine (4) to give 4-(2,4-di- oxy 2,3,4,5,7 , 8-hexahydro-ll·l-piperazo[4,3-d]pyrimidin-8-yl)benzonitrile (intermediate AA(4)). LC-MS (Μ-Η) += 270.2. Preparation

4_(2,4_二气_7,8-Dihydro-5Η-piperacino[4,3-d]pyrimidin-8-yl)benzonitrile

CN makes 4 (2,4_one oxy·2,3,4,5,7,8-hexahydro-1H-pyrano[4,3-d]pyrimidin 8-yl)benzazole (middle) AA(4)) reacts with P〇ci3 as described in Preparation X to give 4-(2,4-digas-7,8-dichloro-511_〇 喃[4,3_d] ringing · 149653.doc -195· 201107311 8-base) clumsy nitrile (preparation aa). LC-MS (M+H)+=306.1 « Preparation AAa 4-(2-Ga-4-(ethylamino)·7,8-dihydro_5H_pyrano[4,3,d]pyrimidine Benzoquinone

4-(2,4-one gas-7,8-dihydro-5Η-η bottom nan [4,3-d] ° -8-8-yl) benzophenone (preparation AA) with ethylamine The reaction was carried out as described in Preparation xa to give 4-(2-carb-4-(ethylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-8-yl. ) Bulk nitrile (preparation AAa). LC-MS (M+H)+=3 15.1.

Preparation AB 2,4-dioxa-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]. Bite

Intermediate AB(2) 3-(4-(Trifluoromethoxy)phenyl)dihydro-2Η-piperidin-4(3H)-one H9653.doc -196- 201107311 Ό ocf3 Using an intermediate χ (2 The procedure used to obtain 3-(4-(difluorodecyloxy)phenyl)dihydro-2hydrazine-piperidin-4(3Η)-one using 4-(trifluoromethoxy)phenyl acid. 1Η NMR (4〇〇MHz, CDC13) δ ppm 7.29 (2 H,d,/=7.05 Hz), 7.19-7.25 (2 H, m), 4.23-4.32 (2 H} m), 3.91-4.04 (2 H, m),

3-84 (1 H, dd, J=8.81, 6.30 Hz), 2.66-2.77 (1 H, m), 2.56-2.63 (1 H,m) 〇Intermediate AB(3) 8-(4-(three Fluoromethoxy)phenyl)-7,8-dihydropyrano[3,oxazin-2,4(3H,5H)-dione

〇

Using the procedure of intermediate X (3), 8-(4-(trifluoromethoxy)phenyl)-7,8-dihydropyrano[3,4-6][1,3]oxazine was obtained. -2,4 (3 511)-dione. *H NMR (500 MHz, DMSO-de) δ ppm 11.98 (1 Η, s), 7.52 (2 Η, d, 7=8.55 Hz), 7.37 (2 H, d, 7=7.93 Hz), 4.45-4.51 (1 H, m), 4.36 (1 H, dd, 7=14.95, 2.14 Hz), 4.00-4.08 (2 H, m), 3.82 (1 H, dd, *7=10.68, 3.36 Hz). Intermediate AB(4) 149653.doc -197. 201107311 8-(4-(Difluorodecyloxy)phenyl)-7,8-dihydro-1H-pyrano[4,3_d] mouth. -2,4(3H,5H)-dione oxime

Ocf3 uses the procedure of intermediate X (4) to obtain 8_(4·(trifluoromethoxy)phenyl> 7,8-dihydro-1Η-piperido[4,3-d]pyrimidine_2, 4(3Η,5η)_ 二嗣.lcms (M+H)+=329_0.

Preparation AB 2,4-digas _8-(4-(tris-1methoxy)phenyl)_7,8_digas_5h slightly sulphur

[4,3-d]pyrimidine CI

〇cf3 uses the procedure of Preparation X to obtain 2,4-dioxa-8-(4-(trifluorodecyloxy)phenyl)-7,8-monohydro-5H-niec and [4,3 d Pyrimidine. LC MS (M+H)+ = = 365.0. Preparation ABa 2-Gas-Indolyl-8-(4-(difluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine_4 _amine «49653.doc • 198- 201107311

NH

To 2,4-dichloro-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d] mouth bit (preparation ab) Methylamine (1 Torr, 2.0 mmol) (2 THF in THF) was added to a solution of EtOAc (EtOAc). The reaction was stirred overnight. The solvent was removed and applied to a silica gel, which was eluted with a gradient of EtOAc/Hex to afford to give hexanes: </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; M-[4,3-d]pyrimidin-4-amine (69.8 mg, 0.194 mmo yield 88%). LC-MS (M+H)+ = 360.0. Preparation ABb 2-Gas-4-((R)-3-Fluoropyridinium-indole-based;)_8_(4-(Trifluoromethoxy)phenyl)·7,8-Iron-1-511- Slightly suffix [4,3-(1]11 密定

〇cf3 to 2,4-dioxa-8-(4-(trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d] ° ΑΒ)(56·4 mg, 0.154 mmol)

DIPEA (67 4 , 0.386 mmol) was added to a solution of MeOH (1545 μM) followed by solid (R)-3·fluoropyrrolidine hydrochloride (21.34 mg, 149653.doc -199· 201107311

0.170 mmol). The reaction was stirred at room temperature. The solvent is removed and applied to the silicone. Dissolve in a gradient of EtOAc/Hex to give a mixture of diastereomers: 2-chloro-4-((R)-3-fluoro.pyrrolidin-1-yl)-8-(4-(trifluoromethoxy)phenyl )_7,8· Dihydro-5H-piperaco[4,3-d]pyrimidine (57.6 mg, 〇138 mm〇1, yield 89%) 〇LC-MS (M+H)+=418.1 〇Preparation AC 2,4-one gas-8-phenyl-5,6,7,8-tetrahydroquinazoline c,X)〇·Intermediate AC(1) 8-phenyl-5,6,7'8 - Tetrahydropyrano[e][l3]. Oxazine-2,4 (called diketone oxime) In a high pressure vessel (75 mL), the 2 phenyl ring has been clarified (ι 5〇〇g' 8.61 mm〇1) and isocyanoguanidine. A solution of gas (〇966 machine, 12 side 〇1) was allowed to stand for 1 hour. The temperature was raised to 130. The reaction mixture was stirred for 2 hours. After cooling to room temperature, the reaction mixture was solidified. The solid residue was dissolved in ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and evaporated and evaporated. Analysis of the oil residue 149653.doc •200· 201107311 Residues' obtained as a white solid 8_phenyl_5,6,7,8_tetrahydro-2//_benzo[e] [ 1,3 ° 嘻 2,4(3/f)-dione (415.0 mg, 1.689 mmol, yield 19.62%) and 4α•phenyl_4α,5,6,7_tetrahydro as a white solid _ 2//__笨笨[e][l'3]°恶π秦-2,4(37^)•二嗣(746.4 mg, 3.04 riimol, yield 35.3〇/〇) 〇8-phenyl-5 ,6,7,8_tetrahydro-2//-benzo[e][i,3]oxazin-2,4(3//)-dione. LC-MS (Μ+Η)+=244· 1.4 NMR (500 MHz , CDC13) δ ppm 8.61 (1H, br s), 7.22-7.38 (3H, m), 7.09-7.19 (2H, m), 3.81 (1H, t, J=A.9 Hz), 2.39-2.63 (2H , m), 2.15 (1H, dddd, */=13.2, 9.8, 6.3, 3.1 Hz), 1.84-1.96 (1H, m), 1.52-1.84 (2H, m). 4α-phenyl-4α,5, 6,7-tetrahydro-2i/-benzo[e][l,3]oxazine-2,4(3/〇-dione. LC-MS (M+H)+=244.1. NMR (500 MHz , CDC13) δ ppm 7.66 (1H, br s), 7.40-7.46 (2H, m), 7.29-7.39 (3H, m), 5.99-6.06 (1H, m), 2.37 (1H, ddd, /=14.0, 3.4, 3.1 Hz), 2.10-2.29 (3H, m), 1.54-1.64 (1H, m), 1.21-1.36 (1H, m) Intermediate AC(2) 8-phenyl-5,6,7, 8-tetrahydroquinazoline-2,4(1//,37/)-dione

Stir 8-phenyl-5,6,7,8-tetrahydro-2-p-benzo[e][i,3]oxazine-2,4 in a high pressure vessel (75 mL) at 100 °C 3/ί)-Dione (415.0 mg, 1.706 149653.doc -201 - 201107311 mmol) in concentrated hydrogen hydroxide (35 mL, 899 mmol) for 6 h. A white precipitate formed during heating. The filtrate was subjected to LC/MS analysis to afford product of the desired mass (M+H) = 243.20. The solvent was removed in vacuo to give 8-phenyl-5,6,7,8-tetrahydrocarbazoline _ 2,4 (1,3//)-dione (435.11 §). 1.706 111111〇1, yield 1〇〇%). ]^- MS (M+H)+=243.2. 'H NMR (500 MHz, DMS 〇 j6) δ ppm 10.2 (2H, br. s.), 7.34 (2H, t, "7=7.5 Hz), 7.26 (1H, t, J = 7.3

Hz), 7.14 (2H, d, /=7.3 Hz), 3.80 (1H, br. s.), 2.32-2.43 (1H, m), 2.15 (1H, ddd, J= 16.9, 10.5, 6.1 Hz), 1.93-2.04 (1H, m), 1.67-1.75 (1H, m), 1.56 (1H, ddd, 7=7.8, 5.2, 2.6 Hz), 1.36 (1H, dt, «7=13.1, 2.7 Hz).

Preparation AC 2,4-dioxa-8-phenyl-5,6,7,8-tetrahydroindole. Sitting

Heating 8_phenyl_5,6,7,8 tetrahydroquinazoline-2,4(1//,3)-two-same (233)mg in a capped vial at 1 l〇 °C , 〇 962 Curry 1), a mixture of bismuth oxychloride (2798 pL, 3 0.0 mmol) and dinonylaniline (933 μΐ, 7.36 mmol) overnight. The reaction mixture was poured into an ice-containing beaker and the inside of the reaction vessel was washed with methyl chloride. Once the ice has completely melted, P places the contents of the beaker into the separatory funnel. The organic layer was separated and the aqueous layer was extracted with dichlorobenzene. The combined organic extracts were dried over anhydrous sodium sulfate and passed. The solvent was removed in vacuo and the residue was purified by EtOAc EtOAc EtOAc EtOAc. Oxazoline (320.3 mg '83%). LC-MS (Μ+Η)+=279·1. NMR (500 MHz, CDC13) δ ppm 7.28 (2H, t, J=1.5 Hz), 7.19-7.24 (1H, m), 6.95 (2H, d, 7=7.3 Hz), 4.23 (1H, t, J= 5.6 Hz), 2.82-2.92 (1H, m), 2.72-2.82 (1H, m), 2.10-2.22 (1H, m), 1.97-2.06 (1H, m), 1.76-1.93 (2H, m). Preparation ACa 2 -Chloro-TV·Ethyl-iV·Mercapto-8-phenyl-5,6,7,8-tetragas 啥&lt;»坐琳-4-amine

To 2,4-dioxa-8-phenyl-5,6,7,8-tetrahydroanthracene. Add #-mercaptoethylamine (0 033 mL '0_386 mmol) to a solution of saponin (53.9 111 §, 0.193 mmol) in methanol (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified eluting eluting eluting eluting eluting eluting 8-tetrahydro saliva "^ siten-4-amine (42. 9 mg, 0.141 mmo yield 72.9%). LC-MS (M+H)+ = 302.2. 'H NMR (500 MHz, CDC13) δ ppm 7.25 (2H, t, /=7.5 Hz), 7.13-7.20 (1H, m), 7.01 (2H, d, J=7.3 Hz), 4.06-4.14 (1H, m), 3.42-3.53 (2H, m), 3.05 (3H, s), 2.56-2.74 (2H, m), 2.17-2.27 (1H, m), 1.76-1.89 (2H, m), 1.52-1.64 ( 1H, m), 1.24 (3H, t, J = 7.2 Hz). Preparation ACb 149653.doc •203 - 201107311 2-Chloro-8-phenyl-5,6,7,8-tetrahydroquinazoline

Heating 2,4-dioxa-8-phenyl-5,6,7,8-tetrahydroquinoxaline (51.9 mg, 0.186 mmol), ammonium chloride (13.0 mg, 0.243) at 90 °C with stirring Mixture of mmol and zinc (130 mg ' 1.988 mmol) in acetone (0·75 mL) and water (0.75 mL) for 2 h. The reaction mixture was filtered through a pad of Celite®. The solvent was removed in vacuo and the residue was partitioned between di-methane and water. The organic layer was separated and the aqueous layer was extracted with di-methane. The combined organic extracts were dried over anhydrous magnesium sulfate and dried. The solvent was removed in vacuo and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc. §, 〇.〇97 111111〇1, yield 52.4%). LC-MS (Μ+Η)+=245·1. NMR (500 MHz, CDC13) δ ppm 8.39 (1H, s), 7.27 (2H, t, J=7.6 Hz), 7.16-7.23 (1H, m), 6.95 (2H, d5 J=7.3 Hz), 4.21 ( 1H} t, J=6.〇Hz), 2.72-2.91 (2H, m), 2.14-2.26 (1H, m), 1.95-2.06 (1H, m), 1.81-1.93 (1H, m), 1.71 1.81 (1H,m) 〇

Preparation AD 2,4-dioxa-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoxaline

F 149653.doc •204· 201107311 Intermediate AD(1) 8-phenyl-5,6,7,8-tetrahydro-2&quot;-benzo[e][1,3]oxazine_2,4( 3/〇-dione

2-(4-Fluorophenyl)cyclohexanone and isocyanomethyl hydrazine gas (0.966 mL, 12 mmol) were reacted in the intermediate AC (1) to give 8-(4-fluorobenzene) as a white solid. -5,6,7,8-tetrahydro-2-indole-benzo[^][1,3]oxazine-2,4(3 ugly)-dione (415.0 mg, 1.689 mmol, yield 19.62) %) and 4α-(4-fluorophenyl)-4α,5,6,7-tetrahydro-2/f-benzo[e][l,3]oxazine-2,4 (white solid) 3//)-dioxime (746.4 mg, 3.04 mmol, yield 35.3%). 8-(4-Fluorophenyl)-5,6,7,8-tetrahydro-2 ugly-benzo[^][1,3]oxazine-2,4(3/〇-dione. LC- MS (M+H)+=262.1. NMR (500 MHz, CDC13) δ ppm 9.61 (1H, br s), 7.10 (2H, dd, J=5.0, 8.5 Hz), 6.98 (2H, distinct triplet, J =8.5 Hz), 3.77 (1H, t, 4.9 Hz), 2.38-2.53 (2H, m), 2.16-2.07 (1H, m), 1.87-1.62 (3H, m) Intermediate AD(2) 8- (4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(17/,3//)-dione

8-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-277-benzo[e][l,3]&quot; 恶 - 149653.doc -205- 201107311 2,4 The solution of (3//)-dione is reacted in the form of intermediate AC(2) to give 8_(4_

Fluorophenyl)-5,6,7,8-tetrahydroindole 〇 琳 -2,4 (l//, 3//)-dione. lc-MS (M+H)+=261.2.

Preparation AD 2,4 - one gas - 8-(4- gas phenyl)-5,6,7,8-tetrazine π sitting

CI

F. A mixture of 8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2,4(17/,3//)-dioxime is reacted as a preparation AC to give 2,4-Digas-8-(4-phenylphenyl)-5,6,7,8-tetrahydropyrazine was not characterized in this step. Preparation ADa 2-chloroethyl-8-(4-fluorophenyl)-#-methyl-5,6,7,8-tetrahydroquinazoline-4-amine

F Stir 2,4-dioxa-8-(4-fluorophenyl)_5,6,7,8-tetrahydroquinazoline (115 mg, 0.387 mmol) and excess hydrazine-mercaptoethylamine at room temperature (〇332 mL, 3 87 mmol) in MeOH (2 mL) The solvent was removed in vacuo to give 2-chloro-ethylethyl-(4-fluorophenyl)-indenyl-5,6,7,8-tetrahydroquinazoline - 149653.doc -206-201107311 4- Amine (124 mg '0.388 mmo yield loo%). LC-MS (M+H)+= 320.2 制备 Preparation AOb 2-chloro-8-(4·fluorophenyldimethyl-5,6,7,8-tetrahydroquinazolin-4-amine

Stir 2,4-Dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg, 0.387 mmol) and excess dimethylamine (1.935 mL) at room temperature , 3.87 mmol) in MeOH (1 mL) 1 hr. The solvent was removed in vacuo to give 2-chloro-8-(4-fluorophenyldimercapto-5,6,7,8-tetrahydroquinazolin-4-amine (118 mg, 0.386 mm. 〇%). LC-MS (M+H)+= 306.2. Preparation AT) c 2-Ga-8-(4-fluorophenyl)-5,6,7,8-tetrahydroindole °

Heating 2,4-dioxa-8-(4-fluorophenyl)-5,6,7,8-tetrafury 坐°°L (115 mg '0.387 mmol), chlorine at 90 °C with stirring A mixture of ammonium (26.9 mg, 0.503 mmol) and aq. (266 mg, 4.06 mmol) in acetone (1 mL) and water (1. The reaction mixture was filtered through a pad of Celite. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The machine layer was separated and the water layer was extracted with digas methane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified eluting elut elut elut

5,6,7,8-Tetrahydroquinazoline (20 111 L, 0.076 111111 〇 1, yield 19.67%). LC-MS (M+H)+=263.2 〇Preparation AE 2,4-dichloro-6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydro This is more than [4,3-d]&quot;

Intermediate AE(1) 2-cyano-2-phenylacetate

To a solution of sodium hydride (24.5 g, 1 - 02 mol) in THF was added benzyl cyanide (50-0 g, 0.426 mol) at -10 °C. The reaction mixture was stirred at the same temperature for 15 minutes. Diethyl carbonate (60.5 g, 0.512 mol) was added to the reaction mixture, and the reaction mixture was allowed to reach room temperature and heated to 40 °C. (Note: the reaction will start suddenly and exotherm). Once the reaction started, the heating path was removed immediately and the reaction mixture was cooled under ice/acetone. The solution was allowed to reach room temperature and stirred for 1 hour. The reaction mixture was cooled to EtOAc (EtOAc) EtOAc (EtOAc) The combined organic layer was washed with water (2 mL), brine (2 mL) Ester (71 .〇. g). The crude compound was used in the next step without further purification. LC-MS (M+H)+ = 190.1. iH nMR (4 〇〇 MHz, DMSO-m) δ ppm 7.45 (5H, m), 5.65 (1H, s) 4 18 (2H, m), 1·18 (3H, t, / = 7.2 Hz). Intermediate AE(:2) 3-Amino-2-phenylpropionate

Nh2 Add palladium/carbon (10./〇, w/w) to a solution of intermediate AE(1) (25.0 g, 0.132 mol) in methanol at room temperature followed by addition of trifluoroacetic acid (2 〇 volume) 50 mL) ^ The reaction mixture was hydrogenated at 3 φ under 5 kg of hydrogen pressure. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was evaporated under reduced pressure and the residue was neutralized with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (2 〇 0 mL &gt;&lt; 4). The combined organic layers were washed with brine (2 mL EtOAc) By column chromatography (Shishijiao, 6〇_12〇目), using 1〇% sterol

One of the chloroform solutions was used as a mobile phase to purify the crude compound to give ethyl 3-amino-2-phenylpropanoate (17 〇 g, 67%) as an oily liquid. LC_MS (M+H) = 194.0. NMR (4 〇〇 MHz, DMSO-state: δ ppm 7.42-7.2 (7H, m), 4.11 (2H, m), 4.09 (1H, m), 3.44 (lH, m), 149653.doc •209· 201107311 3·〇9 (1H, m), 1.15 (3H, t, “7=5.6 Hz). Intermediate AE(3) 3-(3-ethoxy-3-oxopropylpropylamino)-2-benzene Ethyl propyl propionate

To a solution of the intermediate AE(2) (10.0 g, 5 1.7 mmol) in ethanol at room temperature was added ethyl acetate (4.1 g, 40_9 mmol). The reaction mixture was stirred at the same temperature for 18 hours. The solvent was evaporated under reduced pressure, and the crude compound was purified by column chromatography (EtOAc EtOAc (EtOAc) -(3-Ethoxy-3-oxopropylamino)-2-phenylpropionic acid ethyl ester (12.1 g, 80%) 〇LC-MS (M+H)+=294.1 ° 'H NMR (400 MHz, CDC13): δ ppm 7.29 (5H, m), 4.11 (4H, m), 3.76 (1H, m), 3.26 (1H, m), 2.90 (3H, m), 2.44 (2H, m), 1.20 (6H, m) 〇Intermediate AE(4) 3-((3-ethoxy-3-oxopropyl)(4-decyloxyphenylhydra)amino)_2_phenylpropionic acid ethyl ester

Add Κ{〇3(8.4 g, 61·4 mm〇1) to the intermediate AE(3) (15.0g, 51"mm〇1) in 149653.doc -210- 201107311 in acetone at room temperature. Then, p-methoxybenzyl bromide (15.4 g, 76.7 mm〇i) was added. The reaction mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with ethyl acetate (100x3). The combined organic layer was washed with hydrazine brine (1 mL), dried over anhydrous NazSO4, and evaporated under reduced pressure to give a crude material. The crude compound was purified by column chromatography (矽, 6〇_12〇目) using a petroleum ether solution of 3〇% ethyl acetate as the mobile phase to give 3-((3-ethoxy) as an oily liquid. (3 - methoxy propyl) (4-methoxyphenyl fluorenyl) amino) ethyl 2-propenyl propionate (I] 1 g, 6 % by weight). LC-MS (M+H)+ = 414.2. NMR (400 MHz, CDC13)·· δ ppm 7.27 (5H, m), 7.13, (2H, m), 6.82 (2H, m), 4.11 (4H, m), 4·08 (3H, s), 4.06 (1H,m), 3.81 (1H,d, "7=4.0 Hz), 3.79 (1H,d, "7=4.0

Hz ), 3.25 (1H, m), 2.73 (3H, m), 2.43 (2H, m), 1.24 (6H, m). Intermediate AE(5) 1-(4-methoxyphenylhydrazino)_4_sideoxy_5_phenyl phenyl _3-ethyl decanoate

NBuOK (6.5 g, 58. 〇 mm〇i) was added to a cooled solution of the intermediate (4) (12· g, 29.0 mmol) in THF. The reaction mixture was stirred at room temperature for 2 hours. The reaction mass was quenched with water and then the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc EtOAc EtOAc (EtOAc) The crude compound was purified by column chromatography (silica gel, 60-120 mesh) using 25% ethyl acetate petroleum ether as mobile phase to afford 1 _(4-methoxybenzyl) as an oily liquid. )-4-Alkyloxy-5-phenyl.乙乙定-3-曱酸乙 S|(7.1g, 67%) 〇LC-MS (M+H)+=368.2. NMR (400 MHz, CDC13): δ ppm 7.26 (4H, m), 7.15 (2H, m), 6.88 (2H, m), 4.15 (2H, m), 4.09 (3H, s), 3.82 (2H, m ), 3.66 (2H, m), 2.80 (3H, m), 2.40 (1H, m), 1.24 (3H, m). Intermediate AE(6) 6-(4-decyloxyphenyl)-8-phenyl-5,6,7,8-tetrahydro"biti[4,3-cl]»-pyridine-2 ,4(1H,3H)-dione oxime

To a cooled solution of the intermediate AE (5) (7.0 g, 19.0 mmol) in ethanol, i-BuOK (5.3 g, 47.6 mm 〇l) was added followed by urea (2.8 g, 47.6 mmol). The reaction mixture was heated under reflux for a few hours. The reaction mass was quenched with water and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layer was washed with a brine solution (1 mL) and dried over Nad. The crude compound was purified by column chromatography (sand gel, 6〇_12〇目), using the ethyl acetate solution of Xiao 1〇% petroleum mystery as mobile phase to obtain pale yellow 149653.doc •212- 201107311 Solid 6-(4-methoxybenzyl)-8-phenyl-5,6,7,8-tetrahydropyridinium[4,3-d]pyrimidine_2,4(1H,3H )-Dione (4.0 g, 57°/.). LC-MS (Μ+Η)+=364·2. NMR (400 MHz, DMSO-i/(5): δ ppm 11.05 (1 Η, s), 10.60 (1H, s), 7.30 (5H, m), 6.99 (2H, m), 6.77 (2H, m), 3.72 (2H, m), 3.57 (3H, s), 3.44 (1H, m), 3.34 (1H, m), 2.90 (1H, m), 2.51 (2H, m).

Preparation AE 2,4-Dichloro-6-(4-methoxyphenylindenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

A solution of the intermediate AE(6) (2.0 g, 5.5 mmol) and a catalytic amount of DMF in POC13 (20 vol) was heated under reflux for 1 hr. Excess POCI3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 minutes. The aqueous solution was extracted with ethyl acetate (75 mL×3). The combined organic layers were washed with aq. EtOAc EtOAc EtOAc (EtOAc) - decyloxybenzoyl)_8_phenyl_5,6,7,8-tetrahydro&lt;1 pyridine [4,3_4] bite (1.5 g '69%). LC-MS (M+H)+ = 400.0. NMR (400 MHz, CDCI3): δ ppm 7.30 (3H, m), 7.26 (4H, m), 6.81 (2H, m), 4.20 (1H, m), 3.79 (2H, m), 3.72 (3H, s ), 3.68 (2H, m), 3.57 (1H, m), 3.02 (1H, m), 2.98 (1H, m). 149653.doc •213- 201107311 Preparation AEa 2-Ga-6-(4-methoxybenzyl)_N_methyl_8•phenyl_5,6,78 tetrahydropyridinium

To a solution of the preparation AE (1.1 g, 27 mm 〇i) in acetonitrile was added diisopropylethylamine (1. g, 83 〇 〇 1) at room temperature, followed by the addition of methylamine hydrochloride ( 0.28 g, 4" mmol) e The reaction mixture was stirred at room temperature for 18 hr. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (m. 2-gas _6_(4-methoxyphenylhydrazinocarbonyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyridinium-4-amine (〇8 g, 74%) LC-MS (M+H)+ = 395.2 〇!H NMR (4〇〇MHz, DMSO-^): δ ppm 7.29 (4H,m),7·16 (4H,m),6_8〇 (2H, m), 3.93 (1H, m), 3.73 (3H, s), 3.66 (2H, m), 3.57 (1H, m), 3.46 (1H, m), 3.23 (1H, m), 2.67 ( 3H,d,J=4.〇Hz), 2 51 (1H, m). Preparation AEb, 2-chloro-N-ethyl-6-(4-decyloxyphenylhydrazino)_8_phenyl_ 5,6,7,8_tetrahydro" ratio. Ding [4,3-d] pyrimidine bite 4-amine 149653.doc -214. 201107311

Diisopropylethylamine (15 g, 120 Å. 1) was added to a solution of the preparation hydrazine (1·6 g, 4·〇mm〇1) in acetonitrile at room temperature, followed by the addition of ethylamine hydrochloride. (〇.52g, 6.〇mmol). The reaction mixture was (iv) at the same temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (m.p. _Chloro·N_ethyl_6(4-methoxybenzyl)8-group-5,6,7,8-tetrahydro" is defined as [4,3-d]. Bite-4-amine (〇·9 g, 56〇/〇) 〇LC-MS (MH)+=407.0 〇»H NMR (400 MHz, DMSO-d6): δ ppm 7.31-7.12 (7H, m) , 6.83-6.79 (2H, m), 4.47 (1H, ^s)3 4.06 (1H, m), 3.83 (3H, s), 3.66 (2H, m), 3.58 (2H, m), 3.44 (1H, m), 3.20 (1H, m), 3.08 (1H, m), 2.88 (1H, m), 1.25 (3H, d, «7=7.2 Hz). Preparation AEC 2-gas-N,N-dimercapto-6-(4-decyloxyphenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d Pyrimidine-4-amine

Using the procedure of preparation AEb, using diamine to produce 2-chloro-W-dioxin 149653.doc • 215·201107311 -6-(4-methoxyphenylhydrazo)-8-phenyl-5,6 , 7,8-tetrahydrogen. Bis-[4,34]pyrimidin-4-amine. Preparation AEd N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-indolyl-8-phenyl-5,6,7,8-tetrahydro. More than bite and [4,3-d] ° bite-2,4-diamine

The preparation A (〇.229 g, 1.02 mmol), the preparation AEa (0.45 g, 1.14 mmol), Na2CO3 (0.24 g, 2.28 mm 〇1) and xantphos (0.659 g, 1.14) were purged with argon at room temperature. Methyl) solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.59 g, 0.57 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. At 11 baht. The reaction mass was heated under the arm for 24 hours. The reaction was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (1 mL mL 2). The combined organic layers were washed with aq. EtOAc (EtOAc)EtOAc. The crude compound was purified by column chromatography (EtOAc, EtOAc (EtOAc) (EtOAc) 1H-imidazole-1_yl)_3_decyloxyphenyl)_N4_methyl_8phenyl_5,6,7,8-tetrahydron-pyrido[4,3_d]pyrimidine_2,4 II Amine (〇28 g, 3/〇) LC-MS (M+H) = 582.2 ° JH NMR (400 MHz, DMSO-^): δ ppm 9.06 (1H, s), 8.05 (1H, s), 7.71 ( 1H, s), 7.4 (1H, 149653.doc 201107311 S), 7.39-7.06 (11H, m), 6.79 (2H, m), 6.73 (1H, m), 3.93 (1H, m), 3.71 ( 3H, s), 3.62 (2H, m), 3.55 (3H, s), 3.46 (1H, m), 3·26 (1H, "!), 2.92 (3H, d, J = 4.4 Hz). Preparation AEe N2-(4-(4-chloro_1H-imidazole+yl)_3_fluorenylphenyl)_N-heart ethyl_6_(4-decyloxybenzyl)_8_phenyl_5, 67,8-tetrahydropyrido[4,3_d]pyrimidine _ 2,4-diamine

Prepare A (0.442 g, 1.98 mmol), preparation AEb (0.9 g, 2.2 mmol), Na2CO3 (0.467 g, 4.4 mmol) and xantphos (1.27 g, 2.2 mmol) in argon at room temperature Solution in cacao/water (9:1) for 1 hour. Pd(dba)3 (l.l g ' l.i mmol) was added to the reaction mixture and the resulting solution was again purged for a few hours. The reaction mass was heated at 11 ° &lt; t for 24 hours. The reaction material was filtered through a bed of Shixia, and washed with acetic acid. The liquid was evaporated under reduced pressure and the residue was diluted with water. The water &gt; trough solution was extracted with ethyl acetate (1 〇〇 mL x 3). The combined organic layers were washed with brine (1 mL) and dried over anhydrous Naz. The crude compound was purified by column chromatography (gluent, 60-120 mesh) using a mixture of 5 〇 / EtOAc EtOAc as a mobile phase to afford N2-(4-(4- Chloro-1H-imidazole_ι_yloxyphenyl)_N4_ethyl·6_(4_methoxy U9653.doc -217- 201107311 phenylphenyl)-8-phenyl-5,6.,7 , 8-tetrahydropyrido[4,34]pyrimidine-2,4-diamine (0.71 g, 54%) 〇LC-MS (M+H)+=596.2 〇*H NMR (400 MHz, DMSO-J5 ): δ ppm 9.03 (1H, s)5 7.98 (1H, s), 7.71 (1H, s), 7.40 (1H, s), 7.27-7.10 (9H, m), 6.81-6.78 (2H, m), 6.72 (1H, m), 3.91 (1H, m), 3.71 (3H, s), 3.65 (2H, m), 3.56 (3H, s), 3.51-3.49 (3H, m), 3.28 (1H, m) , 2.87 (1H, m), 2.65 (1H, m), 1.18 (3H, t, / = 7.2 Hz). Preparation AEf ^-(3-1-4-(3-methyl-1H-1,2 , 4-trisyl-1-yl)phenyl)-6-(4-methoxyphenylhydrazino)-\4-mercapto-8-phenyl-5,6,7,8-tetrahydropyridine And [4,3-(1]pyrimidine·2,4-diamine

Prepare B (〇175 g, 〇913 mm〇i) with argon at room temperature, _ preparation AEa (0.40 g, l. oi mmol), Na2C〇3 (〇2〇g, 2 〇2 Mm 〇 1) and xantphos (0.585 g, i_〇i mm 〇 1) in dioxane / water (9:1) for 1 hour. Pd(dba)3 (〇.525 g, 0.50 mm〇l) was added to the reaction mixture and the resulting solution was again purged for a few hours. Here. The reaction mass was heated under the arm for 24 hours. The reaction material was passed through a bed of algae with ethyl acetate. The filtrate was decanted under reduced pressure and the residue was diluted with water. The water ☆ solution was extracted with ethyl acetate (丨〇〇 mLχ2). The combined organic layers were washed with EtOAc (EtOAc m. The crude compound was purified by column chromatography (silica gel, 60-120 mesh) using 5% ethyl acetate in methylene methane as mobile phase to afford EtOAc. 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)_6_(4-methoxyindolyl)-N4-methyl-8-benzene Base-5,6,7,8-tetrahydropi-pyridinium [4,3_d]. Mole _ 2,4-diamine (0.24 g, 42%). LC-MS (M+H)+ = 551.1. Preparation AEg N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-tris-ol-1-yl)phenyl)-6-(4-decyloxy Benzoyl)_8_stupyl_5,6,7,8-tetrahydro 0-pyrido[4,3d]pyrimidine-2,4-diamine

Prepare B (〇423 g, 2 2〇mm〇1), preparation AEb (l.〇g, 2.44 mmol), Na2CO3 (0.520 g, 4.89 mmol) and xantphos (1.41) with argon at room temperature. g, 2.44 mmol) in dioxane / water (9:1) for 1 hour. Pd(dba)3 (1.26 g, 1.22 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. In i 1〇. The reaction mass was heated under the arm for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (1 mL), dried over anhydrous Naj. The crude compound was purified by column chromatography (gluent, 6 〇 〇 〇 〇 , , , , , , 149 149 149 149 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 N4-ethyl-N2-(3-fluoro-4-(3-indolyl-1H-1,2,4-triazol-bu)phenyl)-6-(4-decyloxy) _8_phenyl_5,6,78_tetrahydrogen. Bis-[4,3-d]pyrimidine _2,4-diamine (0 70 g, 53%). LC_MS (M+H)+= 565.2 ° Preparation AEh N2-(3_fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-6-(4 -nonyl phenyl fluorenyl) 4-methyl-8-phenyl-5,6,7,8-tetrahydropyridinium[4,3-£1]pyrimidine-2,4-diamine

Prepare C (0.175 g, 0.913 mmol), preparation AEa (0.40 g, i.01 mm〇1), Na2c〇3 (〇.20 g, 2.02 mmol), and argon at room temperature. Xantphos (0.586 g, i. (H mmol) in dioxane / water (9:1) for 1 hour. Add Pd(dba)3 (〇_525 g, 0.50 mm〇l) to the reaction mixture and The resulting solution was again purged for a few hours. The reaction mass was heated under a helium for 24 hours. The reaction was filtered through a pad of Celite (EtOAc) and washed with ethyl acetate. The residue was extracted with EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) The crude compound was purified by using a 5% ethyl acetate gas bath as the mobile phase to obtain N2-(3-fluoro-4) as a white solid 149653.doc • 220·201107311 color solid. -(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-6-(4-decyloxybenzyl)-N4-methyl-8-phenyl-5 , 6,7,8-tetrahydroacridino[4,3-d]pyrimidine-2,4-diamine ( 0.27 g, 51%). LC-MS (M+H)+ = 565.2 ° Preparation AEi N4-ethyl-N2-(3-fluoro-4-(5-mercapto-1H-1,2,4- Triazol-1-yl)phenyl)-6-(4-decyloxyphenyl)-8-phenyl-5,6,7,8-tetrahydropyridinium[4,3-d]pyrimidine

17--2,4-diamine

Prepare c (0.423 g, 2.20 mmol), preparation AEb (1.0 g, 2.44 mmol), Na2CO3 (0.520 g, 4·89 mmol) and xantphos (1.41 g' 2.44 mmol) with argon at room temperature. The solution in dioxin/water (9:1) was used for 1 hour. Pd(dba)3 (1_26 g, 1.22 mmol) was added to the reaction mixture and the resulting solution was again purged for hours, and the reaction mass was heated at i 1 (rc for 24 hours. The reaction mass was filtered through a bed of Celite 8) The organic layer was washed with ethyl acetate (100 mL &lt;3). The combined organic layer was washed with brine (1 〇〇[[ Na2S〇4 was dried and evaporated under reduced pressure to obtain a crude material by &amp; column chromatography (Shishijiao, 6〇_12〇目), using a solution of ethyl acetate in ethyl chloride as the mobile phase. The crude compound was purified to give N4_ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazole-1) as a white solid 149653.doc '221-201107311 -yl)phenyl)-6-(4-decyloxyphenylhydra)_8_phenyl_5,6,7,8-tetrahydroacridino[4,3_d]pyrimidine·2,4-diamine (0·72 g , 54%). LC-MS (M+H)+= 565.4 ° Preparation AEj N2_(4-(4-Gas-1H-imidazo-indolyl)_3_decyloxyphenyl) _n4-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Trifluoromethanesulfonic acid (3 Torr by volume) was added to a solution of the preparation AEd (0.28 g ' 0.48 mmol) in decylbenzene under a dish. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dioxane (25 mL×2), basified with saturated aqueous NaHCO3, and extracted with ethyl acetate (5 mL). The combined organic layer was washed with brine (5 mL EtOAc) _Methoxyphenyl)-N4-methyl-8-phenyl-5,6,7,8-tetrahydroacridine[4'3 (1]3⁄4^疋_2,4-diamine (0.195 g) The crude compound was used in the next step without further purification. LC-MS (M+H)+= 462.2. NMR (400 MHz, DMSO-M): δ ppm 9.03 (1H, s), 8.06 (1H ,s), 7.71 (1H, s), 7.39 (1H, s), 7.27-7.24 (2H, m), 7.18-7.05 (5H, m), 149653.doc -222- 201107311 6.68 (1H,m), 5.76 (1H, s), 3.81 (1H, m), 3.69-3.63 (2H, m), 3.57 (3H, s), 3.22 (1H, m), 2.95 (3H, d, 7=4.0 Hz), 2.84 (1H, m) Preparation AEk N2-(4-(4-Gas-1H-imidazole-4-yl)·3methoxyphenyl phenyl N4ethyl-8_phenyl_5,6,7,8-tetra Hydropyrido[4,3-d]pyrimidine-2,4-diamine

CI

Trifluoromethanesulfonic acid (3·〇 volume) was added to the solution of the preparation AEe (0.25 g, (M2 mmol) in toluene) at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed and the residue was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) The combined organic layers were dried over anhydrous Na.sub.s. -N4-ethyl-8-phenyl-5,6,7,8-tetrahydroacridino[4,3-d]pyrimidine-2,4-diamine (0.19 g). Purification was used in the next step. LC-MS (M+H)+ = 476.2. NMR (400 MHz, DMSO-of (5): δ ppm 9.00 (1H, s), 7.99 (1H, s), 7.71 (1H, s), 7.40 (1H, s), 7.28-7.24 (2H, m), 7.19-7.09 (6H, m), 5-76 (1H, m), 3.70 (1H, m), 3.58 (2H , m)s 3.51 (3H, s), 3.48 149653.doc -223- 201107311 (1Η, m), 2.80 (in, m)5 1.20 (3H, t, J=7&gt;2 (2H,m), 3.25

Hz). Preparation 氟 Fluorine 4 (3-mercapto 1H_1,2,4-triazol-1-yl)phenyl)_N4_methylphenyl-5,6,7,8-tetrahydropyrido[4,3_ (1)pyrimidine_2,4-diamine

F k [Ν,丫 _ ό ～ To the preparation of AEf (0.24 g, 〇·436 mmol) in toluene at the temperature to add the second sylvestre (3.0 volume). The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dioxane (25 mL×2), basified with saturated aqueous NaHCO3, and ethyl acetate (50 mL×2). The combined organic layers were washed with brine (5 mL), dried over anhydrous EtOAc -U,4-triazol-1-yl)phenyl)-N4-mercapto-8-phenyl_5,6,7,8-tetrahydro d-pyrido[4,3-d]pyrimidine-2 The 4-diamine (0.190 g) crude was used in the next step without further purification. LC-MS (M+H)+=431.2. 4 NMR (400 MHz, DMSO): δ ppm 9.13 (1H ,s),8.66 (1H, s), 8.00 (1H, rn), 7.43-7.36 (2H, m), 7.29-7.26 (3H, m), 7 25-7 17 (3H, m), 6.75 (1H , m), 5.78 (1H, m)5 3.83 (1H, m), 3.65 (2H, m), 3.33 (1H, m), 2.94 (3H, d, y=4.4 Hz), 2.33 (3H s). I49653.doc •224· 201107311 Preparation AEm N4_Ethyl-N2-(3·Fluoro_4-(3•Methyl-this 1,2,4_III. Sit_1_yl)phenyl)_

8_Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

At a temperature to the preparation AEg (〇 49〇 g, 〇 8ό8 in benzene

Trifluoromethanesulfonic acid (3. volume) was added to the solution. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with chloroform (5 mL EtOAc) and basified with saturated aqueous NaHCI3 and extracted with ethyl acetate The combined organic layers were washed with brine / EtOAc (EtOAc)EtOAc. Mercapto-1 only-1,2,4-diindole-1-yl)benyl.)-8-phenyl-5,6,7,8-tetrahydroindole ratio 11 and [4,3- d] Pyrimidine-2,4-diamine (0.220 g). The crude compound was used in the next step without further purification. LC-MS (M+H)+ = 445. Preparation AEn N2-(3-Fluoro-4-(5-methyl_1^1-1,2,4-tris-l-yl)phenyl)_]&lt;[4-mercapto- 8 -Phenyl-5,6,7,8-tetrahydrogen ratio. And [4,3-d]°f bite-2,4-diamine

149653.doc • 225-201107311 To a solution of the preparation AEh (0.27 g, 0.490 mmol) in toluene was added trifluoromethanesulfonic acid (3·〇 volume) at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dichloromethane (25 mL &lt;2&gt;), basified with saturated aqueous NaH.sub.3, and extracted with ethyl acetate (5 EtOAc). The combined organic layers were washed with aq. EtOAc (EtOAc EtOAc) Block-1-yl) stupid)-N4-methyl-8-phenyl-5,6,7,8-tetrahydro. More than [4,3-d]pyrimidine 2,4-diamine (0.210 g). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=551·2. Preparation AEa Ν4-ethyl_Ν2-(3-gas-4-(5-fluorenyl-111-1,2,4-tris-l-yl)phenyl)_ 8-phenyl-5, 6,7,8-tetrahydropyrido[4,3-(1]pyrimidine-2,4-diamine

Trifluoromethanesulfonic acid (3.0 vol) was added to a solution of the preparation AEi (0.75 g, 1.32 mmol) in toluene at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with a mono-methane (50 mL×2), basified with saturated aqueous NaHCI 3 and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na.sub.2.sub.4 and dried under reduced pressure 149 653.doc 201107311 to give N4_ethyl s. 2,4-disial_1-yl)phenyl)_8_phenyl_5,6,7,8-tetrahydroindole be compared with [4,3-d]pyrimidine_2,4-diamine (〇 6〇g). The crude compound was used in the next step without further purification. LC-MS (M+H)+ = 445.2. Preparation ΑΈφ 1-(4-(ethylamino)-2-(3-fluoro-4-(3-indolyl-111-1,2,4-trian-1-yl)phenylamino)- 8-phenyl-7,8-dihydroacridazino[4,3-(1]pyrimidin-6(51^)-yl)_

2,2,2-trifluoroethyl ketone

Diethylamine (0.068 g, 0-67 mmol) was added to a solution of the product AEm (0.20 g, 0.449 mmol) in hexanes at 0 C, followed by::: fluoroacetic anhydride (0.14 g, 0.67 mmol) And a catalytic amount of DMAP. The reaction mixture was allowed to reach room temperature and stirred for 18 hours. The reaction mixture was diluted with aq. EtOAc (EtOAc) (EtOAc m. Amino)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benylamino)-8-benyl-7,8-di The hydrogen ratio was determined by [4,3-(1]biting_6(51-1)-yl)_2,2,2-disorganocopper (0.18§, 74%). The crude compound was not further purified. That is used in the next step. LC-MS (M+H)+= 541.2. Preparation AEq 149653.doc 227-201107311 1-(4-(ethylamino)-2-(3-fluoro-4-(5) -mercapto-1H-1,2,4-triazol-1-yl)phenylamino)-8-phenyl-7,8-dihydroacridino[4,3-d]pyrimidine-6 5H)_yl)- 2,2,2-trifluoroethyl ketone

Triethylamine (0.071 g, 0.70 mmol) was added to a solution of the preparation AE(R) (0.21 g, 0.47 mmol) in dioxane under 〇C, followed by the addition of a trifluoroacetate needle (0.15 g '0.70 mmol) And catalytic amount of DMAP. The reaction mixture was allowed to reach room temperature and stirred for 18 hours. The reaction mixture was diluted with aq. EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjj Amino)-2-(3-fluoro-4-(5-methyl-1H-1,2,4-tri. sit-in)-based arylamino)-8-stupyl-7,8-di The hydrogen ratio is determined by [4,3-d]t&gt; mp. -6 (55^) yl)-2,2,2-trifluoroethyl ketone (0.185 g, 73%). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=541·2.

Preparation of AF 2,4-dichloro-6-mercapto-8-phenyl-5,6,7,8-tetrahydro" is more than [4,3_(1]〇密0定

Intermediate AF(1) 149653.doc -228- 201107311 ((3-Ethoxy_3_sideoxypropyl)(methyl)amino)_2_(4-fluorophenyl)ethyl ester

Add K2C〇3 (3.7 g '27.3 mmol) to the intermediate AE(3) (4.0 g, 13.65 mmol) in φ's solution at 〇 °C. Then add the armor (2.3 g ' 16.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous NaCI. The crude compound was purified by column chromatography (Shishijiao '60-120 mesh)' using a 40% ethyl acetate petroleum ether solution as the mobile phase to give 3-((3-ethoxy) as an oily liquid. 3-Oxyloxypropyl)(indenyl)amino)-2-phenylpropionic acid ethyl ester (0.9 φ g, 22%). LC-MS (Μ+Η)+=308·0. NMR (400 MHz, DMSO-J): δ ppm 7.33-7.26 (5Η, m)5 4.07-4.01 (4H, m), 3.83 (1H, m)5 3.07 (1H, m), 2.69-2.52 (2H, m), 2.47-2.41 (3 H,m ), 2.2 1 ( 3 H,s ), 1 · 1 9 - 0 · 1 〇( 6 H,m ). Intermediate AF(2) ethyl 1-mercapto-4-oxo-5-phenylpiperidine-3-carboxylate

149653.doc -229- 201107311 To the cooled solution of the intermediate AF (1) (0.9 g, 2.93 mmol) in THF was added i-BuOK (0.65 g, 5.86 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mass was quenched with water and then the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine (25 mL), dried over anhydrous Na. The crude compound was purified by column chromatography (Shishijiao '60-120 mesh)' using a 1% by weight ethyl acetate petroleum ether solution as a mobile phase to obtain an oxime_methyl_4 side oxygen in the form of an oily liquid. Ethyl 5-phenylpiperidine-3-carboxylate (7.1 g, 67%). LC-MS (M+H)+= 262.2 ° Intermediate AF(3) 6-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 2, 4(1H,3H)-dione

To a cooled solution of the intermediate AF (2) (4.5 g, 17.2 mmol) in ethanol was added ί- Β ιιΟΚ (4·8 g ' 43.1 mmol) followed by urea (2 58 g, 43.1 mmol). The reaction mixture was heated under reflux for 24 hours. The reaction mass was quenched with water and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine (5 mL EtOAc) The crude compound was purified by column chromatography (ruthenium, 6 (M20 mesh) using 1% methanol 149653.doc • 230·201107311 dichloromethacrylate solution as mobile phase to give a pale yellow solid. Methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, 2,4(1H,3H)-dione (2.5 g, 56%). LC -MS (Μ+Η)+=258.2. ιΗ NMR (400 MHz, DMSO-m): δ ppm 11.04 (1H, s), ι〇56 (1H, s), 7.33-7.23 (5H, m), 3.73 (1H, m), 4.75 (1H, 2.83 (1H, m), 2.78 (1H, m), 2.68 (1H, m), 2·22 (3H, s).

Preparation of AF 2,4-dichloro-6-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Cl

A solution of the intermediate AF (3) (4.0 g, 1 5.56 mmol) and a catalytic amount of DMF in POC 13 (20 vol) was heated under reflux for 10 hours. Excess P0C13 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 minutes. The aqueous solution was extracted with ethyl acetate (75 mL &gt;&lt;3). The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc (EtOAc) 8-Phenyl-5,6,7,8-tetrahydro- 0 ratio is defined as [4,3-d]0. Set (1.2 g, 27%). LC-MS (M+H)+ = 294.0. Preparation AFB 2 -Chloro-N,6-dimercapto-8-phenyl-5,6,7,8-tetrahydro 0-bite [4,3-d]e-dimethyl- 4-amine 149653 .doc &lt;231 - 201107311

CI^N Add to the solution of the preparation AF (1 1 r» -&gt; • g ' 3.4 mmol) in acetonitrile at room temperature · monoisopropylethylamine V δ 10 · 2 mmol) Methylamine hydrochloride (0.34 g, 5 1 mmol'). A — ·) The reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (60 </ </ RTI> <RTIgt; _8•Phenyl_5,6,7,8 four gas bites and [4,3-d]pyrimidin-4-amine (0.9 g, 91%). LCMS (M+H)+= 289.2 〇 Preparation AFb 2-chloro-N-ethyl-6-fluorenyl_8_phenyl_5,6,7,8-tetrahydroacridine [4,3d] Xiaodi-4-amine

HN

Diisopropylethylamine (0-52 g, 4 〇mm〇1) was added to a solution of the preparation AF (0.4 g, 1.36 mm 〇1) in acetonitrile at room temperature, followed by the addition of ethylamine hydrochloride (0.16) g '2.0 mmol). The reaction mixture was stirred at the same temperature for 18 hours. The solvent was removed under reduced pressure, and by column chromatography (6 〇 〇 〇 〇 。) /. The petroleum ether solution of ethyl acetate was used as the mobile phase to purify the residue 149653.doc • 232-201107311 Residues to give 2-chloro-N-ethyl-6-methyl-8-phenyl-5 as an off-white solid. 6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.4 g, 97%). LC-MS (M-H)+ = 303.2.

Preparation AG 2,4-chloro- 8-(4-fluorophenyl)-6-(4-methoxyphenylhydrazino)-5,6,7,8-tetrahydropyrido[4,3-d Pyrimidine

CI

F intermediate AG(l) 2-cyano-2-(4-fluorophenyl)acetate

To a solution of sodium hydride (4.2 g, 177.7 mmol) in THF was added EtOAc. The reaction mixture was stirred at the same temperature for 15 minutes. Diethyl carbonate (10.5 g, 88.0 mmol) was added to the reaction mixture and the reaction mixture was allowed to reach room temperature and heated to 40 °C. (Note: the reaction will start suddenly and exotherm). Once the reaction started, the heating path was immediately removed and the reaction mixture was cooled under ice/acetone. The solution was allowed to reach room temperature and stirred for a few hours. The reaction mass is cooled to hydrazine. The mixture was quenched with saturated aqueous sodium sulfate and extracted with ethyl acetate (5 mL). The combined organic layer was washed with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc (4-isophenyl) ethyl acetate (1 〇g). Crude compound without further

Purification is used in the next step. LC-MS (M-H)+ = 206.2. NMR (400 MHz, CDC13) δ ppm 7.44 (2H, m), 7.11 (2H, m), 4.69 (1H, s), 4.27-4.22 (2H, q, /= 7.2 Hz).1.26 (3H,m) . Intermediate AG(2) ethyl 3-amino-2-(4-fluorophenyl)propanoate

Palladium/carbon (10%, w/w) was added to the bath of the intermediate AG(l) (l〇.〇g, 40.0 mmol) in acetic acid at room temperature, followed by the addition of H2S〇4 (〇5 volume) ' 5 mL). The reaction mixture was hydrogenated under a pressure of 5 kg of hydrogen for 18 hours. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was evaporated under reduced pressure and the residue was neutralized with saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (100 mL x 4). The combined organic layers were washed with brine (1 mL) and dried over anhydrous Na NaSO? The crude compound was purified by column chromatography (Shishijiao, 60-120 mesh) using a 1% methanol-nitrogen methane solution as the mobile phase to give the 3-amino group as an oily liquid. 4_Fluorophenyl)propionic acid ethyl ester (6.0 §, 59%). ]^-MS (M+H)+=212.2 〇*H NMR (400 MHz, CDC13): δ ppm 7.26-7.22 (2H, m), 7.04-6.98 (2H, m), 4.15 (2H, m), 3.66 (1H, m), 3.28 (1H, m), 2.99 (1H, m) 丄 20 (3H, m). 149653.doc -234- 201107311 Intermediate AG(3) 3 (3-Ethoxy_3_Sideoxypropylamino)_2-(4-Phenylphenyl)propanoic acid

Ethyl acrylate (丨7 g, 17.0 mmol) was added to a solution of the intermediate AG(2) (3.0 g, 14.0 mmol) in ethanol at room temperature. The reaction mixture was stirred at the same temperature for 18 hours. The solvent was evaporated under reduced pressure, and the crude compound was purified by column chromatography (EtOAc EtOAc (EtOAc) Ethyl (3-ethoxy-3-oxopropylamino)-2-(4-fluorophenyl)propanoate (2.5 g '60%). LC-MS (Μ+Η)+=313·2. 4 NMR (400 MHz, CDC13): δ ppm 7.27-7.21 (2H, m), 7.03-6.97 (2H, m), 4.13 (4H, m), 3.77 (1H, m), 3.23(1H, m), 2.89 (3H, m), 2.48 (2H,m). 1.22 (6H,m) » Intermediate AG(4) 3-((3-ethoxy) -3-oxooxypropyl)(4-decyloxymethyl)amino)_2_(4-fluorophenyl)propanoic acid

149653.doc -235- 201107311 Add K2C03 (1.39 g, 9.6 mmol) to the intermediate AG(3) (2.0 g, 6.42 mmol) in acetone/column at room temperature, followed by the addition of p-methoxy Mercapto bromide (1.68 g, 8.35 mmol). The reaction mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with ethyl acetate (25x2). The combined organic layers were dried <RTI ID=0.0>(Na </ </RTI> <RTI ID=0.0></RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The petroleum ether solution was used as a mobile phase to purify the crude compound to give 3-((3-ethoxy-3-oxopropyl)(4-methoxybenzyl)amino) as an oily liquid. Ethyl 2-(4-fluorophenyl)propanoate (L6 g, 60%). LC-MS (M+H)+ = 432.2. iH NMR (400 MHz, CDC13): δ ppm 7.22 (2H, m), 7.〇9, (2H, m), 6_95 (2H, m), 6.78 (2H, m) 4.14 (4H, m)' 3 · 8〇(3H, s), 3.77 (2H, m), 3.53 (2H, m), 3.16 (1H, m), 2.79 (2H, m), 2_43 (2H, m), 1_24 (6H, m) . Intermediate A G (5) -Fluorophenyl)-1-(4-methoxybenzyl)_4_Sideoxy Ninja-]-carboxylic acid ethyl ester

To the cooled solution of the intermediate AG(4) (1.6 g ' 3.71 mmol) in THF was added i-Bu〇K (0.62 g. 5.56 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mass was quenched with water and then evaporated under reduced pressure. 149653.doc • 236·201107311. The residue was diluted with water and extracted with ethyl acetate (25 mL &lt; The combined organic layers were washed with brine (30 mL)EtOAc The crude compound was purified by column chromatography (tank '60-120 mesh) using 25% ethyl acetate in petroleum ether as the mobile phase to give 5-(4-fluorophenyl)-N (4) as an oily liquid. - decyloxybenzyl) _4_ pendant oxybidine _3-carboxylic acid ethyl ester (io g, 70%). LC-MS (M+H)+ = 386.2. NMR (400 MHz, CDC13): δ ppm 12.0 (1Η, s) 7.26 (4H, m), 7.15 (2H, m), 6.88 (2H, m), 4.15 (2H, m), 3.80 (3H, s) , 3.77 (2H, m), 3.57 (2H, m), 2.80 (1H, m), 2.40 (1H, m), 1.24 (3H, m). Intermediate AG(6) 8-(4-fluorophenyl)-6-(4-decyloxybenzyl)_5,6,7,8-tetrahydro D-pyridyl[4,3-(1] Pyrimidine-2,4(111,311)-dione oxime

To a cooled solution of the intermediate AG (5) (1.0 g, 2.59 mmol) in ethanol, i-BuOK (0.436 g, 3.89 mmol). The reaction mixture was heated under reflux for 24 hours. The reaction mass was quenched with water and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (25 mL). The combined organic layers were washed with a brine solution (3 mL), dried over NaJCU, and evaporated under reduced pressure to afford crude 149653.doc: 237-201107311. The crude compound was purified by column chromatography (gum, 60-120 mesh) using EtOAc EtOAc EtOAc Stupid)_6·(4methoxybenzyl)_5,6,7,8_tetrahydropyrene and [4,3-d] mouth bite_2,4(1Η,3Η)-二西同( 0.6 g '63%). LC-MS (M+H) - 382.2. NMR (400 MHz, DMSO-state: δ ppm 11.06 (1H, s), 1 〇 · 6 〇 (1H, s), 7 35 (2H, m), 7 29 (2H, m), 7.05 (2H, m ), 6.77 (2H, m), 4.05 (1H m), 3.75 (3H, s), 3.53 (1H, m), 3.44 (2H, m), 2.88 (1H, m), 2.65 (2H, m).

Preparation AG 2,4· one gas_8_(4_phenylene)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydropyridinium [4,3- D]pyrimidine

Cl

ο A solution of the intermediate AG(6) (0.6 g, K57 mm〇1) and the catalytic amount in POC13 (20 vol) was heated under reflux for 1 hr. The sputum POCI3 was circulated under reduced pressure. The residue was poured into crushed ice and stirred for 5 minutes. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with aq. EtOAc EtOAc (EtOAc) (4-fluorophenyl)-6-(4-methoxyphenylhydrazino)_5,6,7,8-tetrahydroindolepyridinium[4,3·(1]^σ定(0·35 g LC-MS (Μ+Η)+=418·3. 149653.doc -238- 201107311 Preparation AGa -5,6,7,8-2H(4.fluorophenyl)_6_(4-methoxy Stupid methyl)·ν_methyltetrahydropyrido[4,3-d]pyrimidine_4_amine

. . . at room temperature to prepare the product. ^, 2.39 匪. (10) Production of r* in methanol: 力-isopropylethylamine (〇62 g ' 4.79 mm〇1), followed by the addition of methylamine hydrochloride (0.192 g, 2 87 such as Ύ g 2.87). Remove the solvent under reduced pressure and purify the residue by column chromatography (60-120 mesh) using 35% ethyl acetate in ethyl acetate (4) as mobile phase to give the product as a white solid. (4·fluorophenyl) winter (4methoxybenzyl)-N-methyl_5,6,7,8-tetrahydropyrido[4,3_d] mouth bite_4_amine (0.408 g ' 41%). LC-MS (M+H)+=413.〇., H NMR (400 MHz, DMSO-J6): δ ppm 7.32 (1H, m)3 7.24-7.20 (2H, m), 7.14- 7.06 (4H, m), 6.82 (2H, m), 3.96 (lH, m), 3.72 (3H, s), 3.67 (1H, m), 3.59 (1H, m), 3.50 (1H, m)j 3.2 〇(1H&gt;m)&gt; 2.82 (3H, d, "7=4.0 Hz), 2.80 (1H, m), 2.51 (1H, m). Preparation AGh 2-chloro-N-ethyl- 8-( 4-1 phenyl)-6-(4-methoxy adenyl)_5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine 149653.doc •239· 201107311

CI', N at room temperature to the preparation AG (1.0g, 239 solution added diisopropyl acetate? face to step from the T know dissolved amine hydrochloric acid step (0 23 1 g, 4.79_〇1), then Add B, remove the solvent under the pressure of the factory, and purify the residue by column chromatography (60-120 mesh) using 3G%-35% acetic acid ethyl ruthenium as the mobile phase to obtain a grayish solid. • gas·ν_ethyl winter &amp; phenyl)-6-(4-decyloxybenzyl)_5,6,7,8-tetrahydroindolepyrido[4,3_d]pyrimidine_ 4- Amine (〇·54 g, 54%). LC-MS (M+H)+=427.2. 4 NMR (400 MHz, DMSO-M): δ ppm 7 32 (1H,m), 7.30-7.19 (2H,m), 7.13-7.05 (4H,m) , 6.80 (2H, m), 3.93 (1H, m), 3.71 (3H, s), 3.68-3.48 (5H, m), 3.22 (1H, m), 2.80 (1H, m), 2.68 (1H, m ), 1.15 (3H, m). Preparation AGc 2-chloro-N-ethyl-8-(4-fluorophenyl)_6·(4-methoxyphenylhydrazino)-N-fluorenyl_ 5,6,7,8-tetrahydropyridine And [4,3_(1]pyrimidine_4_amine, N~

F 149653.doc -240- 201107311 Add diisopropylethylamine (0.74 g, 5 7S , s s ) to a solution of preparation AG (1.2 g, 2·87 coffee (4) in decyl alcohol at room temperature ·/5 mmol), then add B

Methylamine (0.2 G g, 3.44 _. 丨). The reaction mixture was i8 h at room temperature (iv). The solvent was removed under reduced pressure, and the residue was purified eluting with EtOAc (EtOAc) 2-Chloro-N-ethyl_8_(4-fluorophenyl)-6-(4-methoxybenzyl)-N-methyl-5,6,7,8-tetrahydroacridine [4,3_pyrimidine-4-amine (0.50 g, 41%). LC-MS (Μ+Η)+=441·2. iH NMr (400 MHz, DMSO-do): δ ppm 7.23-7.16 (4H, m), 7.11-7 〇7 (2H, m), 6.84 (2H, m), 4.10 (1H, m), 3.73 (3H ,s),3 65_ 3.56 (3H,m),3.51-3.40 (3H,m),3.04 (1H,m),2 99 (3H s),2.58 (1H,m),1.11 (3H,t, 7=7.0 Hz). Preparation AGd 2-Gas-4-(3,3-difluoroazetidinyl-1-yl)-8-(4-fluorophenyl)6-(4-methoxy alum bromide... ...-tetrahydrogen pyridine and ^--...nozzle

F to the preparation AG (0.75 g, 1.79 mmol) in the field at room temperature; in methanol, the addition of isopropyl ethylamine (〇58 g, 4 49 mrn〇1, 1 _ each &amp; J money test, monofluoroazetidine (0.25 g, 1.97 mmol). Stir at 149653.doc -241 - 201107311 for 18 hours at room temperature. Remove the solvent under reduced pressure and borrow The residue was purified by column chromatography (60 120 mesh) using a petroleum ether solution of 3% ethyl acetate as a mobile phase to afford 2 _ _ 4 _ (3, 3-difluoro aza Cyclobutanol_1_yl)_8·(4_gasphenyl)_6_(4-methoxyphenylhydrazinium tetrapyridyl[4,3-d]pyrimidine (〇·4 g, 48%). LC -MS (M+H)+= 475.2 〇Ή NMR (400 MHz, CDC13): δ ppm 7.25-7.10 (4Η, m), 6.97-6.82 (2Η, m), 6.80 (2Η, m), 4.52 (4Η , m), 4.07 (1H, m), 3.80 (3H, s), 3.59 (3H, m), 3.36 (1H, m), 2.93 (1H, m), 2.80 (1H, m). , Preparation AG e N2-(4-(4-Ga-1H-imidazol-1-yl)_3_methoxyphenyl)_8_(4-fluorophenyl)-6-(4-methoxybenzyl)_N4_ Methyl _5,6,7,8-tetrahydropyrido[4,3_d]pyrimidine-2,4-diamine

The preparation A (〇.215 g, 0.966 mmol), the preparation AGa (0.40 g, 0.966 mmol), Na2c〇3 (〇.2〇5 g, 1.93 mmol) and xantphos (purified) were purged with argon at room temperature. 0.558 g, 0.966 mmol) of the solution in di-alpha-burn/water (9: i) for 1 hour. Pd(dba)3 (〇.5〇 g, 0.48 mm〇1) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated under HQ for 24 hours. The reaction mass was filtered through a pad of celite and ethyl acetate 149 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The aqueous solution was taken with ethyl acetate = vr. The combined organic layer was washed with brine (~), dried over anhydrous (4), and evaporated under reduced pressure to give a crude compound m (h) (10) (6g_12g). The solution was used as a mobile phase to purify the crude compound to give a white solid. Ν2·(4·(4····························· (4_methoxy acylmethyl)_Ν4_methyl·5,6,7,8•tetrahydrobite bite

[4,3 d] pyridine 2,4-monoamine (〇 20 g, 35%). LC-MS (Μ+Η)+= 600.2 H NMR (400 MHz, OUSO-d6): 6 ppm 9.09 (1H, s), 8-05 (1H, s), 7.72 (1H, s), 7.41 (1H ,s), 7.26-7.22 (2H, m), 7.14-7.05 (7H, m), 6.82-6.75 (2H, m), 3.93 (1H, m), 3.76 (4H, m), 3.74 (2H, m ), 3.72 (1H, m), 3.70 (3H, s), 2.92 (3H, d, /=4.0 Hz), 2.90 (1H, m), 2.70 (1H, m) 〇 Preparation AGf N2-(4- (4-Chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(4-decyloxyphenyl) -5,6,7,8-tetrahydrogen. Bis-pyrene[4,3-(1] pyrimidine-2,4-diamine

Prepare A (0.283 g '1 26 mmol), preparation AGb (0.54 g, 1.26 mmol), Na2CO3 (0.26 g, 2.53 mmol) 149653.doc • 243-201107311 and xantphos with argon at room temperature 0.73 g' i_26 mm 〇 1) The solution in dioxin/water (9:1) for 1 hour. Pd(dba)3 (〇.65 g, 〇63 was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at 11 Torr for 24 hours. The reaction mass 2611 was filtered through a bed of algae. The mixture was washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate (5 mL). The combined organic layer was washed with brine (5 () mL) The 〇4 was dried and evaporated under reduced pressure to give a crude compound, which was purified by column chromatography (EtOAc, 6 〇 丨 〇 〇), using 7% ethyl acetate in dioxane as mobile phase. The crude compound gave N2-(4-(4- gas·ιη-imidazol-1-yl)-3-methoxyphenyl)-N4_ethyl-8-(4-lacylphenyl)- 6-(4-Methoxyphenylhydrazino)_5,6,7,8-tetrahydro 0-pyrido[4,3-d]pyrimidine-2,4-diamine (0.22 g,29./ LC-MS (M+H)+= 614.2. 4 NMR (400 MHz, DMSO-m): δ ppm 9.05 (1H, s), 7.97 (1H, s), 7.72 (1H, s), 7.41 (1H, s), 7.39-7.29 (3H, m), 7.25-7.09 (6H, m), 6.81-6.75 (2H, m), 6.72 (1H, m), 3.93 (1H, m), 3.71 (3H , s) 5 3.67 (1H, m), 3.57 (3H, s), 3.52 (1H, m), 3.49 (2H, m), 3.24 (1H, m) 2.83 (1H, m), 2.65 (1H, m), 1 ·16 (3H, t, ^/==7.2 Hz) 〇 Preparation AGg N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-tris-1 -yl)phenyl)-8-(4-fluorophenyl)-6-(4-methoxybenzyl)-5,6,7,8-tetrahydro.pyridin[4,3-d Pyrimidine-2,4-diamine 149653.doc •244- 201107311

The preparation hydrazine (〇·275 g, 1.43 mmol), preparation AGb (0.68 g, 1.59 mmol), Na2CO3 (0.33 g, 3.19 mmol) and xantphos (0·92 g, 1.59) were purged with argon at room temperature. Ment) solution in dioxane / water (9:1)

1 hour. Pd(dba)3 (〇.82 g, 〇_79 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for a few hours. At 丨1〇. The reaction mass was heated under the arm for 24 hours. The reaction was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (5 mL mL X2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub. The second gas smoldering solution was used as the mobile phase to purify the crude compound to obtain an N4-ethyl group as a grayish white solid called 3 _ s-o-methyl succinyl) phenyl)-8-(4-fluorobenzene) Base f, soil; 6 (4·decyloxybenzyl)-5,6,7,8-tetrahydropyridinium [4,3-d]pyrimidine_2,4_two-faced-amine (0· 6 g, 65%). LC-MS (Μ+Η)+= 5 83.2 ° Ag preparation AGh N4-ethyl-criminal _(3_fluoro-(5-mercapto-1H-1,2,4- Triazole·1-yl)phenyl: ;-(4-fluorobenzyl)-6-(4-oxime oxime methyl)·5,6,7,8-tetrahydropyrido[4,3 d]. dense. -2,4-diamine 149653.doc -245 - 201107311 /^NF HN〆

Prepare C (0.20 g, 1.05 mmol), preparation AGb (0.50 g, 1.17 mmol), Na2C〇3 (0.24 g, 2 34 mm 〇1) and xantphos (0.67 g, argon) at room temperature. I.i7 mm〇i) is two. Solution in cacao/water (9:1) for 1 hour. Pd(dba)3 (0.60 g, 0.58 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for an hour. The reaction mass was heated at 丨1〇〇c for 24 hours. The reaction mixture was filtered through a pad of celite (EtOAc) (EtOAc) (EtOAc) 2 〇 mL) The combined organic layers were dried over anhydrous Na 2 S 〇 4 and evaporated under reduced pressure to give a crude compound. </ RTI> </ RTI> Gas 曱 16 ☆ liquid was used as a mobile phase to purify the crude compound to give N4-ethyl 7.2 (3 gas _4 (5 曱 · ι , , 2 2 心 心 坐 坐)) 8-(4-Fluorophenyl)_6_(4-decyloxyphenyl)-5,6,7,8-tetrahydropyridinium[4,3-d]pyrimidine_2,4--face m Monoamine (0.51 g, 73%). LC-MS (Μ+Η)+= 583.2 « Preparation AGi Ν2_(4_(4ϋ(sodium succinyl)·3·decyloxyphenyl)-N4-B -8-8-(4^phenyl) o-methoxybenzyl) Ν4·methyl·5,6,7,8·tetrahydropyrene [4,3~d]pyrimidine·2,4 -diamine 149653.doc •246- 201107311

The preparation hydrazine (0·25 g, 1 _ 13 mmol), the preparation AGc (0.50 g, 1.13 mmol), Na2CO3 (0.24 g, 2.28 mmol) and xantphos (0.65 g' 1.14) were purged with argon at room temperature. Methyl) solution in dioxin/water (9:1) for 1 hour. Pd(dba)3 (0.60 g '0.560 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for a few hours. The reaction mass was heated at rt 1 (rc). The reaction mixture was filtered over celite and filtered and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The combined organic layer was washed with brine (25 min), dried over anhydrous Naj.sub.4, and evaporated under reduced pressure to give a crude compound. </ RTI> %_i〇% acetic acid ethyl acetonate dichlorohydrazine solution as a mobile phase to purify the crude compound, resulting in gray

5,6,7,8-tetrahydroindene and [4,3_d]pyrimidine _2,4 diamine 45 §, 63%). ° H NMR (400 MHz, DMSO-must): δ

149653.doc LC-MS (M+H)+= 628.2. ΗΗ ppm 9·15 (1H, s), 7.86 (1H, 7.24-7.21 (4Η, m)· 7 -247- 201107311 1.24 (3H, t, /= 7.2 Hz) Preparation AGj N-(4-( 4-gas-in-imidazole_ι·yl)_3-mercaptophenyl)_4_(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6 -(4-methoxyphenylhydrazino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

Prepare A (0.20 g, 0.92 mmol), preparation AGd (〇.40 g, 0.84 _〇1), Na2CO3 (0.18 g, 1_77 mmol) and xantphos (0.48 g, 0.84) with argon at room temperature. Mmol) 1% by weight of solution in dioxane/water (9:1). j&gt;d(dba)3 (0.43 g, 0.420 mmol) was added to the reaction mixture and the resulting solution was again purged for a few hours. At 11 baht. The reaction mass was heated under the arm for 24 hours. The reaction was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The X solution was extracted with ethyl acetate (25 mL &gt;&lt;3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Nat. The crude compound was purified by column chromatography (EtOAc, EtOAc (EtOAc:EtOAc) I_yl)_3·methoxyphenyl)4-(3,3 difluoroazetidinyl-1-yl)-8-(4-fluorophenyl)·6_(4-methoxybenzoate Base)_5,6,7,8 tetrahydrogen 149653.doc 201107311 The ratio of [4,3-d]pyrimidin-2-amine (0.25 g, 49%). LC-MS (M+H)+= 663.0 ° Preparation AGk Ν2·(4-(4-Gas-ΐΗ-嗤丨米嗤丨-yl)_3_methoxyphenyl)_8_(4·Phenylphenyl)- Ν4-methyl_5,6,7,8•tetrahydropyrido[4,3_d]pyrimidine_2,4-diamine

To a solution of the preparation AGe (0.20 g, 0.330 mmol) in toluene was added trifluoromethanesulfonic acid (3 〇 volume) at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with chloroform (25 mL &lt;2&gt;), basified with saturated aqueous NaH.sub.3, and extracted with ethyl acetate (25 mL EtOAc). The combined organic layer was washed with aq. EtOAc (EtOAc) 3-decyloxyphenyl)-8-(4-fluorophenyl)-N4-indolyl-5,6,7,8-tetrahydroacridino[4,3-d]pyrimidine-2,4-di The amine (〇.〇8 g, si%) was used in the next step without further purification. LC-MS (M+H)+ = 480.2. NMR (400 MHz, DMSO-^5): δ ppm 9.36 (1Η, s)} 7.86 (1H, s), 7.75 (1H, s), 7.43 (1H, s), 7.32-7.28 (3H, m), 7.23-7.11 (4H,m), 4.30 (1H, m), 4.02 (1H,m), 3.98 (1H,m),3.7i (1H,m),3.56 (3H,s),3·38 (1H , m), 2.98 (3H, d, "/=4.0 149653.doc -249· 201107311

Hz). Preparation AG1 (BBRC-7610) N2_(4-(4-Gas-1H-flavor-1-yl)-3-decyloxyphenyl)_N4_ethylΐ-Ο-fluorophenyl)_5,6 , 7,8-tetrahydrogen ratio. And [4,3-d] pyrimidine bite -2,4-diamine

Trifluoromethanesulfonic acid (3.0 vol) was added to a solution of the preparation AGf (〇.22 g, 0.35 mmol) in toluene at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dioxane (25 mL×2), basified with saturated aqueous NaHCOs. The combined organic layers were washed with brine (25 mL), dried over anhydrous Najjjjjjjjjjjjjjjjjjjjjjj曱oxyphenyl)-indole 4-ethyl_8_(4-fluorophenyl)_5,6,7,8-tetrahydro. Bis[4,3-d]pyrimidine-2,4-diamine (〇.16 g, 93%). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=494·2. NMR NMR (400 MHz, DMSO-^): δ ppm 9.01 (1H, s), 7.98 (1H, s), 7.72 (1H, s), 7.41 (1H, s), 7.21-7.17 (2H, m) , 7.13-7.05 (4H, m), 6.67 (1H, m), 3.82 (1H, m), 3.66 (2H, m), 3.56 (3H, s), 3.50 (2H, m), 3.20 (ih , m), 2·85 (1H, m), 1.20 (3H, t, J = 7.2 Hz). H9653.doc. -250- 201107311 Preparation AGm N4-ethyl_N2-(3_fluoro-4-(3.methyl-1Η-ι, 2,4·3. sit-1-yl) stupid)_ 8-(4-Fluorophenyl)_5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Difluoromethanesulfonic acid (3.0 vol) was added to the mixture of the preparation AGg (0.40 g, 〇·68 mm 〇1) in toluene at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water. The aqueous solution was washed with decane (20 mL×2), and purified using a saturated NaHCI 3 aqueous solution and extracted with ethyl acetate (25 mL×3). The combined organic layers were washed with brine (25 mL), dried and evaporated under reduced pressure to afford &lt;RTI ID=0.0&gt;&gt; , 2,4-diindole-1-yl)-based)_8_(4_gasphenyl)-5,6,7,8-tetrahydroindolepyrido[4,3-d]pyrimidine_2,4 - Diamine (〇·3〇g, 94%). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=463·2. 4 NMR (400 MHz, DMSO-ru): δ ppm 9.29 (1Η, s), 8.68 (1Η, s)&gt; 8·〇3 (1Η, m ), 7.44-7.37 (2H, m), 7.25-7.21 (2H, m), 7.12-7.07 (2H, m), 6.76 (1H, m), 3.83 (1H, m), 3.68-3.60 (2H, m ), 3.55-3.46 (2H, m)3 3.22 (lH, m), 2.91 (lH, m)s 2·34 (3H, s), i.20 (3H, t, &gt; 7.2 Hz). Preparation AGn I49653.doc 251· 201107311 Ethyl N2-(3-fluoro-4-(5-methyl-1H-1,2,4-tris(yl-1-yl)phenyl) 8_(4-fluoro Stupid)_5,6,7,8_tetrahydropyrido[4,3 d]pyrimidinediamine

Trifluoromethanesulfonic acid (3·〇 volume) was added to a solution of the preparation AGh (0.51 g, 87.87 mmol) in toluene at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with a monooxane (25 mL x 2), then basified with a saturated aqueous NaH.sub.3 solution and extracted with ethyl acetate (25 mL.sup.3). The combined organic layer was washed with a brine solution (25 mL), dried over anhydrous EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 1H-1,2,4-oxadiazole small)phenyl)_8_(4-fluorophenyl)5,6,7,8 tetrahydropyrrole [4'3-_heart 2'4-diamine (0.31 §, 78%). The crude compound was used in the next step without further purification. LC_MS (M+H)+ = 463 2. H NMR (400 MHz, DMSO_岣: δ ppm 9 29 (m, s), 8 68 (ih, s), 8.02 (1H, m), 7.42 (2H, m), 7.23 (2H, m), 7.28-7.10 (2H, m), 6.75 (1H, m), 3.80 (ih, m), 3.67-3.60 (2H, m), 3.55-3.48 (2H, m), 3.22 (1H, m), 2.89 ( 1H,m),2_34 (3H, s), 1.24 (3H,t, "7=7.0 Hz). Preparation AGo(BBRC-4363) N2-(4-(4-Ga-1H-imidazol-1-yl) )_3_decyloxyphenyl)_N4_ethyl_8_ I49653.doc •252. 201107311 (4~Fluorophenyl)_N4_methyl-5,6,7,8-tetrahydropyrido[4,3 -d]pyrimidine-2,4-diamine.

Trifluoromethanesulfonic acid (3. volume) was added to the solution of the preparation AGi (0.10 g, 〇·15 mmol) in toluene at the bottom. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dioxane (10 mL x 2), and purified using a saturated aqueous NaH.sub.3 solution and extracted with ethyl acetate (2 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na. -3-decyloxyphenyl)_th-ethyl_8_(4-fluorophenyl)_N4_methyl_5,6,7,8-tetrahydropyridinium[4,3-d]pyrimidine- 2,4_Diamine (〇·〇3 g). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=508·2. NMR (400 MHz, DMSO-^): δ ppm 7.78 (1H, s)5 7.77 (1H, s), 7.37 (1H, s), 7.20-7.16 (3H, m), 7.12-7.06 (4H, m) , 4.04 (2H, m), 3.80 (1H, m), 3.50 (3H, s), 3.42-3.32 (3H, m), 3.15 (3H, s), 2.81 (1H, m), 1.17 (3H, t , «7=7.2 Hz). Preparation AGp (BBRC-4364) N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)·4·(3,3-difluoroazetidine -1-yl)-8-(4-fluorophenyl)-5,6,7,8-tetrahydro.淀丁和[4,3-d]pyrimidine 149653.doc -253 - 201107311 pyridine-2-amine

To the solution of the preparation AGK〇.2〇 g, 〇_3〇 mmol) in toluene was added trifluoromethyl (tetra) acid (3. G volume) at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. An aqueous solution of methane (10 mL x 2) was taken and purified using a saturated aqueous solution of NaHC(R)3, which was extracted with ethyl acetate (25 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub. Oxyphenyl)-4-(3,3-difluoroazetidin-1-yl)_8_(4-fluorophenyl)-5,6,7,8-tetrahydro&quot; 4,3-(1)pyrimidin-2-amine (0.12 §, 70°/〇).

The crude compound was used in the next step without further purification. LC MS (M+H)+ = 542.0. NMR (400 MHz, DMSO-dosed): δ ppm 9.31 (1H, s), 7.87 (1H, s), 7.73 (1H, s), 7.41 (1H, s), 7.22 (2H, m), 7.15-7.07 (4H, m), 4.74-4.59 (4H, m), 3.97 (1H, m), 3.87 (1H, m), 3.76 (1H, m), 3.51 (3H, s), 3.27 (1;H, m ), 2.83 (1H, m) °

Preparation AH 2,4-Dichloro-8-(4-phenylphenyl)-6-methyl-5,6,7,8-tetrahydro" is more than [4,3-149653.doc •254 - 201107311 dp close bite

Intermediate AH(1) 3-((3-ethoxy-3-oxopropyl)(4-methoxyphenylhydrazino)amino)_2_(4-fluorophenyl)propanoic acid ethyl ester

K2C〇3 (6.38 g, 46.3 mmol) was added to the intermediate AG(3) (12.0 g, 38.5 mmol) in acetone at 〇 ° C, followed by the addition of 峨曱 (6·5 g ' 46.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous layer was extracted with ethyl acetate (5 〇χ 3). The combined organic layers were washed with aq. aq. The crude compound was purified by column chromatography (Shishijiao '60-120 mesh) using a 20% ethyl acetate petroleum ether solution as the mobile phase to give the oily liquid 3_((3_ethoxy)- 3-Phenoxypropyl)(methyl;)amino)_2-phenylpropionic acid ethyl ester (6 〇g '50%). LC_MS (M+H)+=326 2. iH nmR (400 MHz, CDC13): δ ppm 7.01 (2H, m), 6.98, (2H, m), 4.16-4.07 (4H, 149653.doc -255- 201107311 m), 3.77 (1H, m), 3.13 (1H, t, 7=2.4 Hz), 2.75-2.51 (5H, m), 2.17 (3H, s), 1.26-1.19 (6H, m). Intermediate AH(2) 5-(4-fluorophenyl)-1-indenyl-4-yloxy. Σσ定_3_ethyl citrate

To a cooled solution of the intermediate AH (1) (6.0 g, 18.4 mmol) in THF was added i-BuOK (4.1 g &apos; 36.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mass was quenched with water and then the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine (30 mL), dried over anhydrous Na. The crude compound was purified by column chromatography (Shishijiao 60-120 mesh) using a 20% ethyl acetate petroleum ether solution as a mobile phase to afford 5-(4-fluorophenyl) as an oily liquid.

Mercapto-4-oxo piperidine-3-ethyl decanoate (3.0 g, 51%). LC-MS (Μ+Η)+=278·2. NMR (400 MHz, DMSO-): δ ppm 7.35 (1H, m), 7.15 (1H, m), 7.12 (1H, m), 6.98 (1H, m), 4.01 (2H, m), 3.88 (1H, m), 2.60 (1H, m), 2.38 (2H, m)} 2.19 (3H, s), 1.19-1.08 (3H, m). Intermediate AH(3) 8-(4-fluorophenyl)-6-mercapto-5,6,7,8-tetrahydropyridinium and 149653.doc • 256_ 201107311

Add i-BuOK (3.0 g '26.8 mmol) to the middle of the AH(2) (3.0 g 'l〇, 75 mmol) in ethanol, then add urea (ι 6 g, 26.8 mmol) . The reaction mixture was heated under reflux for 36 hours. The reaction mass was quenched with water φ and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine (3 mL), dried over NaHEtOAc, The crude compound was purified by column chromatography (silica gel, 60-120 mesh) using 1% acetonitrile as the mobile phase to give (4-fluorophenyl)-6-fluorenyl- 5 as a pale yellow solid. 6,6,8-tetrahydropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (1.5 g '51%). [e-MS (Μ+Η)+=276·0. 4 NMR (400 MHz, DMSO-c/5): 6 ppm 11.08 (1H, s), 10.59 _ (1H, s), 7.31 (2H, m ), 7.13 (2H, m), 3.74 (1H, m), 3.17 (1H, m), 2.80-2.59 (2H, m), 2.23 (3H, s).

Preparation AH 2,4-dioxa-8-(4-fluorophenyl)_6-fluorenyl-5,6,7,8-tetrahydropyrido[4,3_d]pyrimidine

F 149653.doc • 257· 201107311 A solution of the intermediate AH(3) (1.5 g, 5.45 mmol) and a catalytic amount of DMF in POC13 (20 vol) was heated under reflux for 1 hr. Excess P0C13 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 minutes. The aqueous solution was extracted with ethyl acetate (20 mL×2). The combined organic layer was washed with aq. EtOAc EtOAc (EtOAc (EtOAc) 4-fluorophenyl)-6-mercapto-5,6,7,8-tetrahydroη ratio bite [4,3-d] ° 唆 (0.7 g, 56%) 〇LC-MS (M+ H) += 312_2. Preparation AHa 2_Chloro-8-(4-fluorophenyl)-N,6-diamidino-5,6,7,8-tetrahydropyridin[4,3-d]pyrimidin-4-amine

To a solution of the preparation AH (0.4 g, 1.28 mm 〇i) in decyl alcohol, diisopropylethyl _.33 g, 2 57 mm Qi) was added at room temperature, followed by the addition of methylamine hydrochloride (G. 16 g' 2.57 mmol). The reaction mixture (4) was charged at room temperature. The solvent was removed under reduced pressure and the residue was purified by column chromatography (m.p. "·(4, 基基)_n,6-dimethyl-5,6,7,8-tetrahydroindene and [4,3_d]pyrimidine+amine (〇2〇g,m). LC-MS ( M+H)+=307.2. 149653.doc 258-201107311 Preparation AHh 2-chloro-N-ethyl_8_(4-fluorophenyl)_6_methyl_5,6,7,8-tetrahydro β Bis-pyrene[4,3-d]pyrimidine-4-amine

CI

Diisopropylethylamine (〇_58 g, 4.50 mmol) was added to a solution of the preparation AH (0.7 g, 2.25 mmol) in methanol at room temperature, followed by ethylamine hydrochloride (0.4 g, 4.50) Mm). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and chromatographed by column chromatography (6 〇 _12 〇).

The residue was purified by using 30%·35% of ethyl acetate as the mobile phase to obtain a mobile solid phase. 2' gas was obtained as an off-white solid. 2' gas _ Ν · ethyl o- _ phenyl) · 6-methyl-5,6 , 7,8-tetrahydrogen. More than bite [4,3 secret bite _4_amine (〇, 29%). LC-MS (Μ+Η)+=321·2. Preparation AHc 2-chloro-N-ethyl-8-(4-fluorophenyl)_n,6-di,,anthracepin-5,6,7,8-tetrahydropyridine open [4,3- d] mouth κ amine

CI^n 149653.doc -259* 201107311 To the solution of the preparation Ah (〇_35 gw § 1.1 mmol) in hydrazine was added diisopropylethylamine (0.29 g, 2 9 .. ^ 8 2.2 mmol), the addition of ethyl.67 §, 丨.35 _〇1). The reaction mixture was stirred at room temperature for 18 hours. Remove the solvent under f(iv) and use a column chromatography, chest) to make :35 /. The petroleum ether solution of ethyl acetamate was used as a mobile phase to purify the residue. 2-chloro-N-ethyl (4) fluorophenyl)-N,6-dimethyl-5,6,7 was obtained as an off-white solid. , 8-tetrahydrogen. More than bite [4,3-d] bite _4_ amine (〇 22 g, 58%). LC-MS (M+H)+=333.9 〇Preparation A1 2,4-dichloro-8-(4-fluorophenyl)-7-(4-methoxybenzyl)-5,6,7, 8•tetrahydropyrido[3,4-d]pyrimidine

CI

Intermediate AI(1) 2-Amino 2-(4-fluorophenyl)acetate

F Concentrated sulfuric acid (1 mL) was added to a cooled solution of 2-amino-2-(4-phenylphenyl)acetic acid (1·〇 g, 6.17 mmol) in ethanol over 1 min. The reaction mixture was heated under reflux for 5 hours. The solvent was evaporated under reduced pressure and the residue was diluted with EtOAc EtOAc EtOAc. The organic solution was washed with a saturated aqueous solution of NaHCO3 (15 mL &lt;2), water (20 mL), brine (1 mL), dried over anhydrous NajO4 and evaporated under reduced pressure to give crude compound (oily liquid) The form of 2-amino-2-(4-1phenyl)acetic acid B- (0.75 g, 65%). The crude compound was used in the next step without further purification. </ RTI> <RTIgt; 4.12-4.01 (2H,m), 2.26 (2H,s), 1.12 (3H,t, *7=8.0 Hz). Intermediate AI(2) 4-(2-Ethoxy-1-(4-fluorophenyl)-2-oxoethylamino)butyric acid ethyl ester

Intermediate AI(1) (4.2 g '21.3 mmol) in DMF at room temperature

Carbonate planer (8.3 g '2·25 mmol) was added to the solution followed by 4% methyl butyrate (4_98 g, 2.55 mmol). The reaction mixture was stirred at 7 CTC for 18 hours. The solvent was evaporated under reduced pressure, and the crude compound was purified by column column chromatography (yield: 6 〇 〇 〇 〇 ) ') using 25% ethyl acetate petroleum ether as mobile phase to give a slightly yellow oily liquid. Ethyl 4-(2-ethoxy"-('-phenylphenyl)-2-oxoethoxyethylamino)butanoate (2. 〇g, 3%). LC_MS (M+H)+= 312.2. 4 NMR (400 MHz, CDC13): δ ppm 7.33 (2H, m), 7.06 (2H, m), 4.31 (1H, m), 4.18 (4H, m), 2.63 (1H, m), 2.49 ( 1H,m), 2.35 (2H,m),1.81 (iH,m),124 149653.doc -26,201107311 (6H, m) 〇Intermediate AI(3) 4-((2-ethoxy+( 4-fluorophenyl)-2-oxoethyl)(4-methoxybenzyl)amino)butyrate

PMB

I

EtOOC γ N ^^^^COOEt 9

Add K2C〇3 (7.9 g, 57.8 mmol) to a solution of intermediate AI(2) (15.0 g, 48.23 mmol) in hexane at 〇 ° C, followed by the addition of 4-methoxyphenylhydrazino bromide (14.5 g, 72.3 mmol). At 70. (The reaction mixture was heated for 18 hours. The solvent was removed under reduced pressure, and the residue was evaporated,jjjjjjjjjjjjjjjj NaJO4 was dried 'and evaporated under reduced pressure to give a crude compound. The crude compound was purified by column chromatography (gluent, 60-12 mesh) using a 30% acetic acid ethyl alcohol as a mobile phase. Ethyl 4-((2-ethoxy-indole-(4-fluorophenyl)-2-oxoethyl)(4-methoxyphenylhydrazinyl)amino)butyrate as an oily liquid 12.0 g, 60%) LC-MS (Μ+Η) + 432.2. NMR (400 MHz, CDC13): δ ppm 7.30 (2 Η, m), 7.22 (2H, m), 7.01 (2H, m), 6.99 (2H, m), 4.52 (1H, s), 4.22 (2H, m), 4.04 (2H, m), 3.79 (5H, m), 3.61 (1H, m), 2.71 (1H, m), 2.57 ( 1H, m), 2.20 (1H, m)5 2.07 (1H, m), 1.70 (2H,m), 1.28 (3H,m, J=7.2 Hz), 1.20 (3H,m,·7=7.2 Hz) Intermediate AI(4) 149653.doc •262- 201107311 2_(4-Fluorophenyl H-(4-decyloxybenzyl)-3-oxooxypiperidine_4-carboxylic acid ethyl ester

NBuOK (6·2 g, 55.5 mmol) was added to the cooled solution φ of the intermediate AI (3) (12. g, 27.7 mmol) in THF. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was purified eluting with EtOAc EtOAc EtOAc EtOAc Evaporation under pressure to obtain a crude compound. The crude compound was purified by column chromatography (j. 4_Fluorophenyl)_ i-(4-decyloxybenzyl)-3-trioxybenzoate-4-carboxylate (7.0 g, • 67%). LC-MS (M+H) +=386.2. NMR (400 MHz, CDC13): δ ppm 12.02 (1H, s), 7.43 (2H, m), 7.15 (2H, m), 7.04 (2H, m), 6.84 (2H, m), 4.23 (2H, q, &gt; 7.2 Hz), 4.05 (1H, s), 3.79 (3H, s), 3.65 (1H, d, J = 13.6 Hz), 3.22 (1H, d, J = 13.6 Hz), 2.92 (1H,m), 2.35 (3H,m),1_32 (3H,t, "/=7.2 Hz). Intermediate AI(:5) 8-(4-fluorophenyl) _7_(4_methoxybenzyl)_5,6,7,8 tetrahydroindolepyrido[3,4-d]pyrimidine-2,4(1Η,3Η)-dione 149653.doc -263 - 201107311

To the cooled solution of intermediate AI (4) (7.0 g' 18_1 mmol) in ethanol was added i-BuOK (5.0 g, 45.4 mmol) followed by urea (2 7 g,

45.4 mmol). The reaction mixture was heated under reflux for 18 hours. The reaction mass was quenched with water and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine (75 mL), dried over Nad. The crude compound was purified by column chromatography (ruthenium, 6 〇 〇 〇 〇 , , , , , , , , , 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 纯化 纯化 纯化 纯化 纯化 纯化 纯化 纯化 纯化-(4-fluorophenyl)-7-(4-decyloxybenzyl)_5,6,7,8-tetrahydroindene and [3,4-d]pyridinium-2 4 (1h, 3H Diketone (3 〇g, 45%). [C MS (M+H) = 382.0. iH nMR (40〇mHz, DMSO-柳δ ppm U'08 (1H' S), 1().44 UH, s), 7.26-7.17 (6H, m), 6.92 (2H, ym) 4 36 (1H, s)' 3.75 (3H, s), 3.73 (1H, d, */=13.2 Hz) 3.58 (1H, d, J 13,2 Hz), 2.63 (2H, m), 2.51 (1H , m), 2.35 (1H, m). Preparation A1 2,4·difluorophenyl)-7-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine 149653.doc -264- 201107311

A solution of ten substances AI (5) (2.0 g, 5.24 mmol) and a catalytic amount of dmf in POC13 (30 vol) was heated at 85 ° C for 18 hours. Excess POCI3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 15 minutes. The aqueous solution was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with aq. EtOAc (aq. EtOAc) 4-Fluorophenyl)-7-(4-decyloxyphenyl)- 5,6,7,8-tetrahydroindole is a bit of [3,4-d]pyrimidine (1.4 g, crude). LC-MS (M+H)+ = 418.0. Preparation Ala 2-Gas-N-Ethyl-8-(4-fluorophenyl)-7-(4-methoxyphenylindenyl)_5,6,7,8-tetrahydroanthracene [3,4 -d]°Bite-4-amine

Add diisopropylethylamine (〇43 g, 3 35 mm〇1) to the solution of the preparation ΑΙ(〇·7 g, 1.67 mmol) in decyl alcohol, followed by the addition of ethylamine hydrochloride. Salt (0.27 g, 3.35 mm 〇i). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ethyl 8·(4fluorophenyl)_7· (4-methoxyphenylhydrazinyl)-tetrahydropyridinium^^^pyrazine (0.36 g, 50%) in an off-white solid. -MS (M+H)+=427.2. 丨η NMR: (400 MHz, DMSO-^): δ ppm 7.38 (2Η, m), 7.30 (2H, m), 7.20-7-13 (4H, m) , 6.88 (2H, m), 4.45 (1H, s), 3.73 (3H, s), 3.45 (1H, m), 3.40-3.34 (3H, m), 2.88 (1H&gt; m), 2.42 (2H, m ), 1.16 (3H, t, /= 7.2 Hz) Preparation Alh 2-Gas-N-Ethyl-8-(4-fluorophenyl)-7-(4-methoxyphenylindenyl)_N_曱Base 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-amine

To a solution of the preparation AI (0.7 g, 1.67 mmol) in methanol was added diisopropylethylamine (〇·43 g' 3 3 mm〇1), followed by the addition of ethylguanamine hydrochloride. Salt (0.19 g ' 3.35 mmol). The reaction mixture was stirred at room temperature for 18 hours. "The solvent was removed under reduced pressure and purified by column chromatography (6 </ </ </ </ </ "> </ </ </ </ </ "> </ "> 2, gas·N_ethyl_8_(4-fluorophenyl)-7-(4-methoxyphenylindenyl)·Ν·曱yl_5,6,7, as an off-white solid. 8_tetrahydroacridino[3,4_d]pyrimidine (0·40 g, 54%). LC_MS (Μ+Η)+=44ι 2. n hall 149653.doc -266· 201107311

(400 MHz, DMSO-d6) δ ppm 7.49 (2H, m), 7.19-7.14 (4H m)' 6.87 (2H, m), 4.42 (1H, s), 3.73 (3H, s), 3.55 (2H, m), 3.42 (1H, m), 3.21 (1H, m), 3.04 (3H, s), 2.95 (2H, m), 2.56 (1H, m), 2.25 (1H, m), 1.16 (3H, t , "7 = 7.2 Hz). Preparations Alcl and Alc2 2-Gas-8-(4-fluorophenyl)_4-((Han-3)-fluoro 0-pyridyl q-yl)_7_(4-_methoxybenzyl)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To a solution of the preparation AI (〇.7〇g, 16 mmol) in methanol was added isopropylethylamine (〇4〇g, 3 35 mm〇1) to /m, followed by addition (S )-3-fluoropyrrolidine (〇25 g, 2 14 mm〇1). The reaction mixture was stirred at room temperature for 18 hours. "The solvent was removed under reduced pressure" and the residue was purified by preparative HpLc to give 2-[Lambda]-8-(4-fluorophenyl)-4-((R) 3-fluoropyridin-1-yl)-7-(4-methoxybenzyl)_5,6,7,8-tetrahydro 0-pyrido[3,4_d]pyrimidine (0.150 g ' 37 % and 190 mg, 43%).

Alcl: LC-MS (Μ+Η)+ = 471·1. NMR (400 MHz, gas-simple PPm 7.48 (2H, m), 7.15 (2H, m), 7.01 (2H, m), 6.83 (2H, m)&gt; 5.30 (1H, m), 4.43 (1H , s), 3.97-3.90 (4H, m), 3.88-3·72 (4H, m), 3.65 (1H, m), 3.17 (1H, m), 3.02 (2H, m), 149653.doc -267 - 201107311 2.33 (2H, m), 1.95 (1H, m) AIc2: LC-MS (M+H)+=471.1. NMR (400 MHz, chloroform δ ppm 7.28 (2H, m), 7.18 (2H, m ), 6.99 (2H, m), 6.84 (2H, m), 5.30 (1H, m), 4.58 (1H, s), 4.20-4.11 (2H, m), 3.97- 3.80 (6H, m)3 3.69 ( 1H, m), 3.35 (1H, m), 2.88 (2H, m), 2.35 (1H, m), 2.17 (1H, m), 2.05 (1H, m) 〇Preparation Aid 2 - gas - 8-( 4-fluorobenzyl)-4-((S)-3- °bi bit _ i _yl)_7_(4-methoxybenzyl)-5,6,7,8-tetrahydroacridine Ο

To a solution of the preparation hydrazine (0·70 g, 1.6 mm 〇i) in methanol was added diisopropylethylamine (〇43 g, 3 35 mni〇i) at room temperature, followed by addition of (R)- 3-fluoropyrrolidine (〇25 g, 2 2 mm〇1). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative HpL (: to give 2- gas _8_(4-fluorophenyl)_4_((s)_3 fluoropyrrolidine)-- (4-Methoxybenzyl)-5,6,7,8-tetrahydro.pyridinium[3,4-d]pyrimidine (0.150 g, 37% and 190 mg, 43%). LC-MS (M+H) dec = 471.2. Preparation Ale Ν2·(4-(4·chloro-1H-imidazol-1-yl)_3_methoxyphenyl)_N4_ethyl_8_ 149653.doc 201107311 (4-Fluorophenyl)-7-(4-decyloxybenzyl)·5,6,7,8-tetrahydro 0-pyrido[3,4-d]pyrimidine-2,4-di amine

Prepare A (0.36 g, 0.845 mmol), Preparation Ala (0.189 g, 0.845 mmol), Na2CO3 (0.179 g, 1.69 mmol) and xantphos (0.488 g, 0.845 mmol) with argon at room temperature A solution of dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.870 g, 0.845 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for a few hours. Here. The reaction mass was heated under the arm for 24 hours. The reaction mass was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (5 mL EtOAc) The crude compound was purified by column chromatography (60-120 mesh) using 20% ethyl acetate EtOAc/yield as mobile phase to afford N2-(4-chloro-1H -imidazol-1-yl)-3-methoxyphenyl)_N4_ethyl_ 8-(4-fluorophenyl)·7_(4·decyloxyphenyl)·5,6,7,8 _ Tetrahydro-α-pyrido[3,4-d]pyrimidine-2,4-diamine (ο.% g, 58%). LC_MS (Μ+Η)+=6ΐ4 2. *H NMR (400 MHz, DMSO-^): δ ppm 8.96 (1Η, s), 7.79 (1H, s), 7.74 (lHj s), 7.43 (1H, s)5 7.33 (2H, m), 7.20 ( 6H, m), 6.89 (2H, m), 6.80 (1H, m), 4.44 (1H, s), 3.74 (3H, s), 149653.doc -269· 201107311 3.66 (3H, s), 3.50 (4 , m), 2.90 (1H, m), 2·33 (3H, m), 1·24 (3H, t, "7 = 7.2 Hz). Preparation Alf N2-(4-(4-chloro-1H-flavor) sitting on a small base)_3_methoxyphenyl)_n4-ethyl-8-(4-fluorophenyl)-7-(4-anthracene Oxyphenyl fluorenyl)_N4_methyl_5,6,7,8-tetrahydro 0 ratio. And [3,4-d]pyrimidine _2,4_ diamine

Preparation A (0.20 g, 0.90 mmol), preparation AIB (0.41 g, 0.90 mmol), Na2CO3 (0-192 g, 1.8 c mmol) and xantphos (0.525 g, 0.90 mm〇i) were purged with mouse gas at ambient temperature. ) A solution of dioxazole in water/water (9:1) for 1 hour. Pd(dba)3 (〇.470 g, 〇_45 mmol) was added to the reaction mixture, and the resulting solution was again purged with argon for a few hours. The reaction mass was heated at 1 Torr &gt; c for 24 hours. The reaction was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (5 mL mL x 3). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na? The crude compound was purified by tube chromatography (60-120 mesh) using 30% acetic acid ethyl ether cold liquid as the mobile phase to give a white solid as a 4' chloro-1H-imidazole. Oxyphenyl)-N4-ethyl-8_(4-hydrophenyl)-7-(4-methoxybenzyl)-N4-mercapto_5,6,7,8-tetrahydrobite 149653.doc 201107311 And [3,4-d]pyrimidine-2,4-diamine (〇·34 g, 59°/〇). This compound was used in the next step without further analysis. LC-MS (Μ+Η)+=628·2. Preparation Alg N-(4-(4-Chloro-1H-imidazo-bu)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoro n ratio σ -1- -1-yl)-7-(4-methylazinophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

Prepare A (0.070 g, 0.319 mmol), preparative AIcl (0.150 g, 0.319 mmol), Na2CO3 (0.067 g, 0.63 mmol) and xantphos (0.184 g, 0.319 mmol) in argon at room temperature A solution of methane/water (9:1) for 1 hour. Pd(dba)3 (0.165 g, 0.159 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at 1 Torr for 24 hours. The reaction mixture was passed through a pad of Celite (CeUte) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with a brine solution (2 hrs), dried over anhydrous <RTIgt; Purification of the crude compound using a 5 wt% ethyl acetate petroleum ether solution as the mobile phase to give a gray

149653.doc -271 · 201107311

5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine _2-amine (〇] g, 48%" lc_ms (M+H)+=658.2 制备 Preparation Alh

Prepare A (〇〇9 g, 〇4〇4 mm〇1), preparation AAc2 (0.190 g, 0.404 mmol), Na2CO3 (0.085 g, 0.80 mmol) and xantphos (0.230) with argon at room temperature. g, 0.404 mm 〇 1) solution in dioxane / water (9:1), time. Pd(dba)3 (0.209 g, 0.202 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for a few hours. The reaction mass was heated under 丨丨〇 &lt;&gt;c for 24 hours. The reaction mixture was filtered through a pad of Celite (EtOAc) andEtOAc. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (20 mL &gt;&lt;3). The combined organic layers were washed with brine (2 mL EtOAc) The crude compound was purified by column chromatography (6〇_12〇目) using a petroleum ether solution of 5〇% ethyl acetate in ethyl acetate as the mobile phase to give N-yield as ash 149653.doc -272-201107311 white solid. (4-(4-Gas-1H-flavor-1-yl)-3-decyloxy)-8-(4-fluorophenyl)-4-((11)-3-1° pyridine Small base)-7-(4-decyloxyphenyl)- 5,6,7,8-tetrahydro-pyrido[3,4-d] ° dense η定_2_amine (〇· 120 g , 48%). LC-MS (M+H)+ = 538. Preparation Aik N2-(4-(4-Ga-1Η-»m. sit-1-yl)_3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-5, 6,7,8-tetrahydropyrido[3,4-(1]pyrimidine-2,4-diamine

Trifluorodecanesulfonic acid (3.0 vol) was added to a solution of the preparation AMe (0.3 g, 0.489 mmol) in toluene at ambient temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with di-methane (25 mL x 2), basified with saturated aqueous NaH.sub.3, and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (50 mL), dried EtOAc EtOAc EtOAc _ yl)-3-methoxyphenyl)_N4_ethyl_8_(4-fluorophenyl)_5,6,7,8-tetrahydropyridin[3,4-d] °密'^疋-2,4-Diamine (〇.2〇g). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=494·2. Preparation All (Example 1) N2-(4-(4-Ga-1H-imidazolyl)_3_methoxyphenyl)_N4_ethyl_8_ 149653.doc •273 · 201107311 (4·fluorophenyl) -N4-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4 diamine

To the solution of the preparation AIF (〇.34〇 g, 0.541 mmol) in toluene was added trifluorodecanesulfonic acid (3 〇 volume) at room temperature. The reaction mixture was heated under reflux for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with dioxane (10 mL &lt;2), basified with a saturated aqueous NaHCO.sub.3, and extracted with ethyl acetate (2 m m. The combined organic layer was washed with brine (25 mL), dried over anhydrous NaHHjjjjjjjjjjjjjjjjjjjjjjjj -decyloxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl·5,6,7,8-tetrahydropyrido[3,4-d]- 2,4-Diamine (0.20 g). The crude compound was used in the next step without further purification. LC-MS (Μ+Η)+=508·2. NMR (400 MHz, DMSO-m): δ ppm 9.05 (1H, s), 7.78 (1H, 0' 7.74 (1H, s), 7.43 (1H, s), 7.32 (2H, m), 7.21 - 7.0 ( 5H, m), 4.85 (1H, s), 3.59 (3H, s), 3.49 (2H, m), 3.05 (3H, s), 2.68 (2H, m), 2.51 (2H, m), 1.22 (3H , t, J = 7.2 Hz). Preparation Aim N-(4-(4-Ga-1H-imidazol-1-yl)_3-decyloxyphenyl)_8 (4fluorophenyl)_ 4_((R )-3-fluoropyrrolidin-1_yl)_5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine 149653.doc 201107311

In the middle, the intermediate AIg (〇.12〇 g, 〇·182 mmol) was added to toluene in toluene (3.0 vol.). Put the reaction mixture back

Grab the heat for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with chloroform (1 mL EtOAc) and basified with saturated aqueous NaHCO3 and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (2 mL EtOAc EtOAc. 8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydropyridinium [3,4- d] ° bite-2-amine (0.040 g, 50%). LC-MS (M+H)+ = 538.2. Preparation Ain N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3 -败" than slightly biting -1-yl)-5,6,7,8-tetrahydro η than bite [3,4-d]*&gt; sessile-2-amine

F 149653.doc -275-201107311 Trifluorodecanesulfonic acid (3·〇 volume) was added to the mixture of the preparation AIh (0.12 〇 g, 0.182 mmol) in toluene to the dish. The reaction mixture was heated back to _ - j /;, L α for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was washed with a mono-methane (10 mL×2), basified with saturated NaIic(3) water, and then extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine <RTI ID=0.0>(2 </RTI> <RTI ID=0.0> 8-(4-fluorophenyl)_4_((R)-3-fluoro.pyrrolidine_ι_yl)_5,6,7,8-tetrahydro. Ratio °疋[3,4-d] Pyrimidine_2-amine (0.045 g, 51%). LC-MS (Μ+Η)+= 538.2.

Preparation AJ 2 -milo-4-(methylamino)-8-phenyl-7,8-dihydroindole.坐琳-8-ol ΗΝ〆

Intermediate AJ(1) 2-Ga-6-(Amidino-based bite-4-decanoic acid vinegar ΗΝ〆

喊 Shout at 2,6-dichloro at 〇°C. Hunig's base (3.7 mL) was added dropwise to a mixture of guanidine phthalate (2 g) and guanamine hydrochloride (0.72 g) in CH2C12 (48 mL). The reaction mixture was stirred under ice bath for 1 min U9653.doc • 276-201107311, then stirred at room temperature for a few hours. The solvent was removed in vacuo and directly passed through Biotage using 40 〇 / 〇 - 600% Et 〇 Ac / hexane (1 〇〇〇 mL) followed by 9% C^Ch/lO% Me 〇H (4 L) The title compound (1 8 g) was obtained as a white solid. These fractions were combined and evaporated in vacuo. Some white solids formed during solvent removal. The title compound (18 g, very white solid) was obtained as a white solid. MS (Μ+Η)+=202·0〇. Intermediate AJ(2) 2-Gas-N-Methoxy_N_methyl·6_(Methylaminopyridine _4_Proline _(1)〆

To a solution of 2_gas_6_(decylamino)pyrimidine-4-decanoate (1.95 g) and hydrazine, hydrazine-dimethylhydroxylamine hydrochloride via a dropping funnel over 30 minutes at -20 °c 1.887 g, 19.34 mmol) of isopropylmagnesium hydride (23.60 mL, 47.2 mmol) was added dropwise to a suspension in THF at -10. (The reaction mixture was stirred for 40 minutes. The title compound was obtained from EtOAc EtOAc EtOAc EtOAc LC-MS (M+H)+= 231.01 ° Intermediate AJ(3) 5-Bromo-2-a-N-methoxy-N-mercapto-6-(decyl)pyrimidine-4- Guanamine

149653.doc -277- 201107311 A solution of 2-oxo-N-methoxy-N-methyl-6-(methylamino)pyrimidine-4-carboxamide (959 mg) in MeCN (21 mL) NBS (814 mg) was added and the reaction mixture was heated at 60 ° C for 8 hours. The solvent was removed and the residue was purified eluting elut elut elut elut elut elut elut elut LC-MS (M+H)+ = 310.95. Intermediate AJ(4) 2 -Gas-N-decyloxy-N-indenyl-6-(methylamino)-5-Vinyl-mouthed 4-曱 guanamine HN〆

Heating 5-bromo-2-gas-N-decyloxy-N-methyl-6-(decylamino)- stilbene-4-carboxamide (1 〇〇 mg), tributyl at 95 ° C A solution of (vinyl)stannane (113 mg), hydrazine (23 mg) in terpene (1.6 mL) was taken for 12 hrs and solvent was removed. The residue was purified by EtOAc EtOAc EtOAc EtOAc LC-MS (M+H)+= 257.06 ° Intermediate AJ(5) (2-Ga-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone

2-Chloro-N-methoxy-N-methyl-6-(decylamino)-5-vinyl-glycidyl-4-carboxamide (136 mg) in THF (1.8 mL) 149653.doc • 278-201107311 phenylmagnesium bromide (1 M THF solution, 1.3 mL) was added dropwise, and the reaction mixture was stirred at 0 ° C for 30 min. The reaction was taken with EtOAc EtOAc EtOAc EtOAc. LC-MS (M+H)+= 274.03 ° Intermediate AJ(6) 1-(2-chloro-6-(decylamino)-5-vinylpyrimidin-4-yl)-1-phenylidene 3-ene-1-alcohol _

To a solution of (2-gas-6-(methylamino)-5-vinylpyrimidin-4-yl)(phenyl)methanone (142 mg) in THF (2.6 mL) at room temperature Dilylpropyl bromide (1.0 M in THF, 1.1 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction was treated with EtOAc / EtOAc (EtOAc)EtOAc. LC-MS (Μ-Η20+Η)+= 298.18 °

Preparation AJ 2 -Chloro-4-(methylamino)-8-phenyl-7,8-dihydroanthracene-8-ol

To 1-(2-Chloro-6-(methylamino)-5-ethenyloxy-4-yl)-1-phenylbutyl 149653.doc 279· 201107311 dilute-1 -alcohol (60 mg) Gibs I (16 mg) was added to the solution in benzene (5 mL), and the reaction mixture was heated at 85 ° C for 1 hour. The solvent was removed and the residue was purified eluting elut elut elut elut elut elut elut elut 4 NMR (500 MHz, CDC13) δ ppm 7.4 (5H, m), 6.25 (1H, m), 6.07 (1H, m), 5.14 (1H, br. S), 4.52 (1H, s), 3.10 (3H , d&lt; J=5.0 Hz), 2.99 (2H, m). 13C NMR (125 MHz, CDC13) 164.32, 159.38, 1 58.85, 144.15, 128.24, 128.02, 127.83, 125.51, 117.54, 108.14, 60.51, 38.50 and 28.57. (:151115(:1&gt;^〇1111]^8(]\4+11) The calculated value is 288.0904; the experimental value is 288.0899.

Preparation AK 2 -Gas-4-(indenyl)-8-phenyl-5,6,7,8-tetrazirconium-8-ol

To 2-ox-4-(methylamino)-8-phenyl-7,8-dihydroindole. 5% Pd/C (6 mg) was added to a solution of EtOAc (20 mg) in EtOAc (5 mL). The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.

!H NMR (500 MHz, CDC13) δ ppm 7.3 (5Η, m), 4.9 (1H, br. S), 4.02 (1H, s), 3.14 (3H, br. S), 1.5-2.5 (6H, m 〇13C NMR (125 MHz, CDC13) 164.82, 162.72, 158.56, 146.54, 128.02, 127.37, 126.72, 110.92, 74.81, 37.58, 28.61, 21.89, 17.47. HRMS (M+H) of C丨5H, 7C1N30 is calculated as 29〇1〇6〇; 149653.doc •280- 201107311

The experimental value is 290.1052. Preparation AL 2-Gas-4-(decylamino)-7-phenyl-6,7-hydro-5H-cyclopenta[d]pyrimidine-

The conversion from the phase (5) shown in Preparation AJ/AK was used to dilute from 2, 6 gas.曱-4-曱 曱 曱 制备 制备 制备 制备 2 2 · _ _ _ _ _ _ _ _ _ _ _ _ _ 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 : : : : : : : : : : : Indoleamine replaces methylamine hydrochloride and uses M equivalent of Hughes test; intermediate AL (6). Use bromoethylmagnesium bromide instead of bromoallyl magnesium. 4 (500 MHz, CDC13) δ ppm 7.3 (5H, m), 3.28 (6H, s), 1.5-3.4 (5H, m). 13C NMR (125 MHz, CDC13) 174.66, 161,76, 159.58, 144.61, 128.49, 127.58, 125.35, 113.92, 82.86 , 41.07, 39.00, 28.59. The calculated HRMS (M+H) for CuHnClNW is 290.1060;

Preparation AM (6S,7S)-2-chloro-4-(diguanylamino)-7-phenyl-6,7-dihydro-5H_cyclopenta[d]pyrimidin-6-ol

149653.doc •281 201107311 Intermediate AM(1) 2-Gas-N,N-Dimethyl-7-phenyl-5H-cyclopenta[d]pyrimidin-4-amine

To 2-H--4-(monodecyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]»midine-7-ol (85 mg) in i-PrOH An HCl solution (1 Μ solution) of HCl was added to the solution in (5 mL) and the reaction mixture was heated at 80 ° C for 3 hours. The solution was cloudy and turned into a clear yellow solution by the end of the reaction. The solvent was removed and the title compound (50 mg). LC-MS (M-H20+H)+= 272.07 〇

Preparation AM (6S,7S)-2-Gas-4-(diamidoamine)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]&quot;

To 2-gas-N,N-dimercapto-7-phenyl-5H-cyclopenta[d] at room temperature. dense. Add a solution of borazine-dimethyl sulphur complex in THF (2.0 Μ solution, 0.41 mL) to a solution of 4-amine (113 mg) in THF (2 mL), and stir the reaction mixture at room temperature 5 hour. Water (0.50 mL) was carefully added, followed by 3 〇〇/0 Η2〇2 (〇·50 mL) and 1 N NaOH (1 mL). 5 mL of EtOAc was added and the reaction mixture was stirred at 149 653. doc - 282 - The crude product was purified by EtOAc (EtOAc): LC-MS (Μ-Η20+Η)+=290·05.

Preparation AN 2-Gas-4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

Intermediate AN(1) 2,4-Dichloro-6-(1-phenylvinyl)pyrimidin-5-yl)nonanol cr

Heating at 100 ° (: 2,4,6-tri-pyrimidin-5-yl)methanol (1.1 §), 1-phenylidenecarboxylic acid (0.8 g), hydrazine (0.3 g), sodium carbonate ( 1.64 g) A mixture of hydrazine (14 mL) and water (3 mL) for 12 s. Water was added, then ethyl acetate was added and the aqueous layer was extracted with ethyl acetate (3 times) Drying over sodium sulphate, EtOAc (EtOAc)EtOAc. Μ+Η)+=281·02« NMR (500 MHz, gas-d) δ ppm 7·5 (5Η, m), 6.01 (1Η, s), 5.67 (1H, s), 4.62 (2H, s Intermediate AN(2) 149653.doc -283- 201107311 2,4-Dichloro-6-(1-phenylvinyl)pyrimidine_5-formaldehyde

Add PCC (600 mg) and 4A MS (600 mg) to a solution of 2,4-diox-6-(1-phenylvinyl)pyrimidin-5-yl) decyl alcohol (327 mg) in CH2Cl2. The reaction mixture was stirred at room temperature for 3 minutes. A few minutes after the addition of pec, the solution turned from dark to dark brown. The reaction mixture was filtered with EtOAc EtOAc EtOAc. Intermediate AN(3) l-(2,4-digas-6-(i-phenylidenevinyl)pyrimidine-5-yl)propan-2-ene-indole-alcohol

2,4·di-gas-6-(1-phenylvinyl)pyrimidine_5·formaldehyde (2〇〇φ 2-gas-4-(decylamino)__笨基-6 at _78 C ,7-dihydro-5H-cyclopenta[d]pyrimidine-

Preparation AN 149653.doc -284- 201107311 5-ketone

To 1-(2,4-dioxa-6-(1-phenylethenyl)" benzoate-5-yl)prop-2-en-1-ol (20 mg) in CH2C12 (6.5 mL) Gibs 11 catalyst (6 mg) was added to the solution, and the reaction mixture was heated under reflux for 3 Torr. The solvent was removed and the residue was dissolved in EtOAc (4 mL) and &lt;RTIgt;&lt;/RTI&gt; The reaction mixture was stirred under a hydrogen balloon for 35 minutes. The helium balloon was removed, followed by a Hughes test (23 μΙ〇, followed by the addition of guanamine (36 pL, 2 Μ methanol solution). The reaction mixture was stirred at room temperature for 10 minutes and the solvent was removed. The title compound (6.6 mg, yield 37%) eluted elute elute elute elute elute 1-7.4 (5H,m), 4.45 (1H, dd, J=3.0, 8.0 Hz), 3.24 (1H, dd, J=8.0, 19.5 Hz), 3.20 (3H, s), 3.19 (3H, s) , 2.71 (1H, dd, J=3.0, 19.5 Hz). 13C NMR (125 MHz, gas-d-d) δ 203· 12,186.69, 166.52, 159.93, 139.88 129.16 (2C), 127.73 (2C), 127.59, 110.98, 46_50, 45.48 and 27.53. (: 141'113 (: 1 &gt; 13〇1111)^8 (1^+printed value is 274.0742; experimental value is 274.0741.

Preparation AO 3-methoxy-4-(1-methyl-1Η-°bizozol-4-yl)aniline 149653.doc • 285-201107311

A solution of diethyl 1-methyl-1H-pyrazol-4-yl-anoate and DMF of 4·bromo-3-yloxynitrobenzene was heated under reflux with Pd (dppf) and Κ4〇3 overnight. The obtained product was reduced with MeOH / EtOAc / EtOAc. LC-MS (M+H)+ = 204.2. Towel NMR (400 MHz, DMSO-m) · δ ppm 7.84 (1H, s), 7.66 (1H, s), 7.19 (1H, J=8.2 Hz, d), 6.29 (1H, s), 6.18 (1H , J—2.0, 8.2 Hz, dd), 5.31 (2H, br s), 3.80 (3H, s), 3.75 (3H, s). EXAMPLES Example 1 N2-(3-methoxy small (3-methyl-1H-1,2,4-triazole) phenyl)-N4_methyl-7 _styl-hydro-5:1-ring Pentacene [(1]. M..-2,4-diamine

The method of Example 74 was used to combine the preparations of &amp;&gt; with 3-methoxy-4-(3-methyl-lH-l,2,4-tris-l-yl)aniline (preparation D)'. N2-(3-methoxy-4-(3-methyl-lH_1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6,7-dihydro -5H-cycloindole [d] oxime -2,4-diamine (Example 1). LC-MS (M+H)+ = 428.2. 'Η NMR (500 MHz, OD) δ ppm 8.95 (1 H, br. s.), 7.72 (1 d, /=2.14 Hz), 7.65 (1 H, d, J=8.55 Hz), 7.37-7 -42 (2 H,m), 7.30-7.34 (1 H, m), 7.26 (2 H,d, -286- 149653.doc 201107311 7=7.02 Hz), 7.22 (1 H, dd, 7=8.85, 2.14 Hz), 4.42-4.48 (1 H, m), 3.93 (3 H, s), 3.16 (3 H, s), 2.88-2.96 (1 H, m), 2.72-2.83 (2 H, m), 2.46 (3 H, s), 2.12-2.21 (1 H, m). Example 2 Ή2-β-Μ,-4-(3- ψ Μ-1Η-1,2,4-^ Μ S)-N4- 7-phenyl-6,7-dihydro-5Η-cyclopenta[ d]pyrimidine-2,4-diamine

Using the method of Example 74, the preparation Ga was combined with 3-fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenylamine (Preparation B) to give N2-(3). -fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-indolyl-7-phenyl-6,7-dihydro-5H-cyclo Pentans[d]pyrimidine-2,4-diamine (Example 2). LC-MS (M+H)+ = 416.2. NMR (500 MHz, MeOD) δ ppm 8.77 (1 H, br. s·), 7.95 (1 H, dd, /=13.43, 2.14 Hz), 1.11 (1 H, t, J=S.70 Hz), 7.48 (1 H, dd, /=8.85, 1.53 Hz), 7.40 (2 H, t, J=7AS Hz), 7.33 (1 H, t, J=7.48 Hz), 7.28 (2 H, d, /= 7.02 Hz), 4.49 (1 H, dd, J=7.63, 4.58 Hz), 3.18 (3 H, s), 2.88-2.98 (1 H, m), 2.77-2.86 (2 H,m), 2.46 (3 H, s), 2.14-2.24 (1 H, m) 〇 Example 3 N2-(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl) -N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine 149653.doc •287 · 201107311

The preparation Ga was combined with 3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-bu)anilide (preparation C) using the method of Example 74 to give N2-(3- Fluoro-4_(5_mercapto-1H-1's heart-small-snyl)phenyl)_N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d] carcinoma Bite-2,4.diamine (Example 3). LC_MS (Μ+Η)+=416·2. NMR (500 MHz, MeOD) δ ppm 8.11 (1 H, s), 7.99 (1 H, dd, /=12.51, 1.83 Hz), 7.51-7.60 (2 H, m), 7.41 (2 H, t, J =7.48 Hz), 7.31-7.36 (1 H, m)5 7.28 (2 H, d, J=7.02 Hz), 4.47-4.54 (1 H, m), 2.90-3.00 (1 H, m), 2.76- 2_87 (2 H,m), 2.42 (3 H,s), 2.15-2.26 (1 H,m).

Example 3A N2-(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-phenyl-6,7-dihydro - 5H-cyclopenta[d] mouth bite-2,4-diamine

Example 3 was isolated by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ '3〇% EtOH/heptane/0.1% DEA) to give a yellowish opaque glass!^2_(3 _Fluoro_4_(5-methyltriazole-fluorenyl)phenyl)-N-methyl-7-phenyl-67 dihydro-5H cyclopentapyrimidine_2,4-diamine (first dissolved out) 'Enantiomer A'. LC-MS (M+H)+ = 416.2. 149653.doc 201107311 *H NMR (500 MHz, MeOD) δ ppm 8.15 (1 H, dd, /=13.73, 2.14 Hz), 8.03 (1 H, s), 7.36-7.42 (1 H, m), 7.28- 7.36 (3 H, m), 7.16-7.26 (3 H, m), 4.21 (1 H, t, /=7.78 Hz), 3.07-3.13 (3 H, m), 2.78-2.88 (1 H, m) , 2.59-2.76 (2 H, m), 2.35-2.41 (3 H, m), 1.99-2.13 (1 H, m) °

Example 3B N2-(3-Fluoro-4-(5-methyl-lH-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-phenyl-6J-dihydrogen -5H-cyclopenta[d]pyrimidine-2,4-diamine

Preparation of N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-indolyl-7-phenyl according to Zixi/3d Enantiomer B of -6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, but the second self-preferential HPLC column elution of the enantiomer 'Yellow yellow opaque glass. LC-MS (M+H)+=416.2 » ]H NMR (500 MHz, MeOD) δ ppm 8.17 (1 H, dd, 7=13.89, 2.29 Hz), 8.02 (1 H, s), 7.28-7.46 ( 4 H, m)5 7.16-7.27 (3 H, m), 4.19 (1 H, t, J=7.78 Hz), 3.05-3.16 (3 H, m), 2.78-2.89 (1 H, m), 2.57 -2.78 (2 H, m), 2.33-2.48 (3 H, m), 1.99-2.17 (1 H, m). Example 4 n2-(4_(4·Chloro-1H-isazole small group μ% methoxyphenyl)_N'N4·dimethyl-7-phenyl-6,7-dihydro-51{-cyclopentane And [(1] pyrimidine-2,4-diamine 149653.doc •289· 201107311

Add 2-dioxanyl-7-phenyl-6,7-diargon-5//-cyclopenta[d]pyrimidin-4-amine (200 mg '0.731 mmol) to 4-(4-gas A solution of -1//-imidazol-1-yl)-3-decyloxyaniline (163 mg, 0.731 mmol) in THF (1 mL) andEtOAc. The reaction mixture was stirred at 75 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give iV2-(4-(4-gas-1//-imidazol-1-yl)-3-methoxyphenyldimethyl-7-phenyl-6,7-dihydro-5 //-Cyclopenta[d]pyrimidine-2,4-diamine TFA salt (180.7 mg, 0.308 mmol, yield 42.2%). LC-MS (M+H)+= 461.2. NMR (500 MHz, CDC13 δ ppm 11.12 (1H, s), 7.98-8.17 (2H, m), 7.09-7.56 (6H, m), 7.01-7.09 (1H, m), 4.31-4.52 (2H, m), 3.97 (1H, s), 3.81-3.89 (2H, m), 3.45-3.55 (2H, m), 3.32-3.43 (3H, m), 3.16-3.29 (2H, m), 2.81- 3.03 (1H, m), 2.56- 2.75 (2H, m), 2.07-2.32 (2H, m).

Examples 4A and 4B (S)-N2-(4-(4-Ga-1H-imidazole-l-yl μ% methoxyphenyl)_N4,N4_dimethyl-7-benyl-6,7- Wind-511-cyclopenta[(^]-biting-2,4-diamine oxime (R)-N2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxybenzene Base)_Ν4 Ν4_ dimethyl-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine_2&gt;4_diamine 149653.doc •290· 201107311

Purification of Han 2-(4-(4-Ga-1)-imidazole-buyl)_3.methoxyphenyl)-oxime, #-dimethyl-7-phenyl_6,7 using palmitic SFC _ Dihydro _5 / / _ cyclopenta [d] pyrimidine _ 2, 4- diamine racemic mixture (a discharge of a, to obtain peak A (real ί not to) and peak Β (' Μ Μ). SFC method: Chiralpak ¢^4 (4.6^50 mm, 5

μΜ), 35% methanol in 〇02 (0·1〇/〇diethylamine), 35t:, flow rate 2 〇mL/min, maintained for 22 minutes, 268 nm absorbance, injection of 5 2 mg/mL solution in methanol (Multiple stack injections) 'iR (peak A) = 5.1 minutes, iR (peak B) = 18.1 minutes. The individual stereoisomers were not determined (absolute stereochemistry of Violet®. The LC-MS and 1H NMR data of the isolated enantiomers were identical to those of the racemate (Example 4). Example 5 Ν2-( 4-(4-Chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)-indole 4-ethyl-indole 4-methyl-7-phenyl-6,7-dihydro-5Η-cyclo Penta[d] shouting bite-2,4-diamine

2-Ga-7V-Ethyl-iV-indolyl-7-phenyl-6,7-dihydro-5//-cyclopenta[d] oxime-4-amine (160 mg' 0.556 mmol Add to a solution of 4-(4-Gas-1//-imidazol-1-yl)-3-decyloxyaniline (124 mg, 0.556 mmol) in THF (1.5 mL) . The reaction mixture was stirred at 8 (TC) at 149653.doc -291.201107311. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions afforded W-(4-(4- gas-1//-imidazole) 1-yl)-3-decyloxyphenylethyl-7^-methyl-7-phenyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-di Amine (85.3 mg, 0.171 mmol' yield 30.7%). LC-MS (M+H), 475.2. 丨H NMR (500 MHz, CDC13) δ ppm 7.49-7.61 (1 H, m), 7.38 (1 Η , br. s.), 7.23 - 7.34 (6 Η, m), 7.13 (1 Η, d, J = 8.5 Hz), 7.05 (1 H, s), 4.35 (1 H, dd, /=9.3, 4.1 Hz), 3.69-3.82 (4 H, m), 3.47 (2 H, br. s.), 3.27-3.38 (4 H, m), 3-11-3.23 (1 H, m), 2.56-2.72 ( 1 H, m), 2.24 (1 H, ddd, &gt; 9.0, 4.4, 4.3 Hz), 1.31 (3 H, t, "7 = 7.2 Hz).

Examples 5A and 5B (S)-N2-(4-(4-Chloro-1H-imidazo-i-yl)-3-f-oxyphenyl)-N4_ethyl, N-methyl-7-phenyl- 6,7-Dihydro-5 Η-cyclopenta[Technology] mouth bite 4-diamine and (R)-N2-(4-(4-chloro-1H-imidazo-i-yl)_3_methoxy Phenyl) N4 ethyl, N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

Purification gas · imidazolyl) using a palmitic SFC) _3_methyl phenyl phenyl) · ethyl yl -7 phenyl -6,7 _ dihydro _ Cyclopenta [outer pyridine 2, 4 -Diamine racemic mixture (not 5) 'Get peak a (real you μ) and peak B (not to be. SFC method: Chiralpak 〇j_h (4.6x25〇_, $ 149653.doc -292 · 201107311 μΜ) '(: 35% methanol in 〇2 (0.1% diethylamine), 35 ° C, flow rate 2.0 mL / min, maintained for 22 minutes, 268 nm absorbance, injection of 5 called 2 mg / mL solution in methanol ( Multiple stack injections), (peak A) = 4_5 minutes, (peak B) = 16.7 minutes. The absolute stereochemistry of the individual enantiomers (see μ and 55) was not determined. Separation of the enantiomers The LC-MS and 1h NMR analytical data were identical to the racemic (5). Example 6 4-(azetidin-1 -yl)-indole-(4·(4-chloro-1Η-imidazole- 1-yl)-3-methoxybenzyl)-7-phenyl-6, fluorene-dioxin-5 Η-cyclic guanidine

4-(Azetidine-fluorenyl)-, gas_7_phenyl_6,7-dihydro-5//_cyclopenta[d] is dense. Add (162 mg, 0.567 mmol) to 4-(4-gas-oxime/f-mipropion-i-yl)-3-nonyloxyaniline (127 mg, 0.567 mmol) in acetic acid (1.ooo mL) and In a solution of THF (1 mL). The reaction mixture was heated overnight at 8 (TC). The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions afforded 4-(azetidinium-imidazole-diyl)-3-methoxy-phenyl). _Stupyl _6,7_Dihydro _5 ugly _cyclopenta[d]pyrimidine_2_amine

ΙΤΑ salt (39.2 mg, 0.066 mmol, yield 11.66%). LC-MS (M+H)+=473.2 ° lH NMR (500 MHz, CDC13) δ ppm 11.44 (1H, s), 7.94 (1H, d, J=1.5 Hz), 7.52 (1H, d, 7=2.1 Hz), 7.27-7.44 (4H, m), 6.96-7.23 (3H, m), 4.64 (3H, br s), 4.38 149653.doc -293- 201107311 (2H, d, "7=7·6 Hz) , 3.83 (2H, s), 3.29-3.52 (1H, m), 3.11 (1H, d, "7=7.9 Hz), 2.98 (1H, s), 2.62-2.76 (1H, m), 2.57

(2H, s), 2.14-2.38 (2H, m) 〇Examples 6A and 6B (S)-4-(azetidin-i-yl), _(4(4·chloro·1H_imidazole small group) ) Winter methyloxy) 7-phenyl-6,7-dihydro-[Η-cyclopenta[d].密定-2-Amine (R)-4·(azetidin-1-yl), _(4_(4-chloro]1 imidazolidinyl)-3-methoxyphenyl)-7- Phenyl-6,7-dihydro·5H_cyclopenta[d]pyrimidin-2-amine

Purification of 4-(azetidinyl-indenyl)_#_(4_(4·chloro-1//-imidazol-1-yl)-3-methoxyphenyl)_7_ using palmitic SFC Phenyl-6,7-dihydro-5-open cyclopenta[d]pyrimidin-2-amine racemic mixture (Hungarian illusion, get peak eight (real ^) and peak B (# Hungry) SFC method: Chiralpak 〇JH(4 6χ25〇_ ' $ μΜ) '(:35% sterol in 〇2 (0.1〇/〇diethylamine), 35〇c, flow rate 2 〇mL/min, maintain 3〇 Minute '268 nm absorbance, 5 of this 2 mg/mL solution in 50:50 methanol/gas imitation (multiple stack injections), iR (peak A) = 5 9 minutes, iR (peak B) = 24.6 minutes. The absolute stereochemistry of the individual enantiomers (Shen-Hung and 65) was not determined. The 1η NMR data of the separated enantiomers were identical to those of the racemic (Shen-Hung (5). 149653.doc -294 - 201107311 N2-(4-(4-Chloro-1H-imidazolyl)_3·roxyphenyl)_n4_methyl_7phenyl &amp; Ί 一风-5 Η -戍戍和[d]. Bite-2,4-diamine

2_gas·ΑΓ_methyl_7_phenyl_6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine (833 mg, 3.21 mm〇1) in a 350 mL high pressure vessel And a solution of 4(4 chloro)indole-1-yl)-3-nonoxylamine (717.9 mg, 3.21 〇1) in thF (5.6 mL) and acetic acid (5.6 mL) at 85. (The next time the mixture was heated overnight. The solvent was removed in vacuo and the residue was taken up in di-methane methane and washed with saturated aqueous sodium bicarbonate. The organic phase was separated and extracted with dichloromethane. Dry over magnesium sulfate and filter. The solvent was removed in vacuo and the residue was purified by chromatography eluting eluting eluting eluting eluting )__/y4_methyl_7-stupyl_6,7-dihydro-5//-cyclopenta[d] spray-determined-2,4-diamine, which is subjected to 4-(4-chloro- 1//- 〇 〇 _ ι ι · · · · 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Pure iV2-(4-(4-gas-li/-imidazol-1-yl)-3-methoxyphenyl)-indole_methyl_7_benthyl-6,7-anthracene -5//-cyclopenta[d]e succinyl-2,4-diamine (673.5 mg, 47%). LC-MS (M+H)+= 446.9. A NMR (5 〇〇 MHz, CDC13) δ ppm 7.99 (1Η, d, J=1.8 Hz), 7.48 (1H, s), 7.27-7.33 (2H, m), 7.16-7.24 (3H, m), 6.96-7.07 (3H,m), 6.71 (1H, dd, ^=8.4, 1.7 Hz), 4.50 (1H, Br s), 4.20 (1H, s), 3.48 (3H, s), 149653.doc •295- 201107311 3.11 (3H, d, */=4.9 Hz), 2.59-2.79 (3H, m), 2.01-2.13 (1H, m). Example 7A and (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)_N4-methyl-7-phenyl- 6,7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine(R)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxy Phenyl)_N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine

Purification of #2-(4-(4-Ga-1/f-imidazol-1-yl)-3-methoxyphenyl)-7V4-indolyl-7 using palmar supercritical fluid chromatography (SFC) -Phenyl-6,7-dihydro-5//-cyclopenta[d] mouth. A racemic mixture of 2,4-diamine (92 mg, 0.206 mmol, from ss. 7) gave 28.4 mg of peak A (not 7 J) and 27.4 mg of peak Β (: Τ^ 7 ugly). SFC method: Chiralpak OJ-H (3〇x250 mm, 5 μΜ), 40% sterol (0.1% diethylamine) in C〇2, 35 ° C, flow rate 70 mL/min, maintained for 16 minutes '268 nm absorbance , 1 mL of 15 mg/mL solution in sterol (multiple stack injections), (peak Α) = 5.00 min, iR (peak B) = 12.3 min. The absolute stereochemistry of the individual enantiomers (Shen 7J and 75) was not determined. The LC-MS and 1H NMR analytical data of the separated enantiomers were identical to those of the racemic compound. Example 8 149653.doc -296-201107311 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_N4_cyclopropyl·7_phenyl-6,7- Diqi- 5Η-cycloindole[d] σ-Bite-2,4-diamine

To 2-Chloro-indole-cyclopropyl-7-phenyl-6,7-dihydro-5Η-cyclopenta[(^ shout&lt;7-4-amine (175 mg' 0.612 mmol) with 4- Concentrated sulfuric acid (0.046 mL, 0.857 mmol) was added to a mixture of <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The mixture was stirred at 97 ° C for 20 hours. After cooling to room temperature, 1 mL of EtOAc was added, washed with saturated NaHC03 / water and water, dried over Na 2 EtOAc, and finally removed. Via Biotage (12 g, The residue was purified with EtOAc (EtOAc:EtOAc) 7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (200 mg, 0.423 mmol, yield 69.1%). LC-MS (Μ+Η)+=473·10. 4 NMR (500 MHz, CDC13) δ ppm 7.81 (1 H, d, J=1.8 Hz), 7.51 (1 H, d5 J=1.5 Hz), 7.44 (1 H, s), 7.27-7.35 (2 H, m) , 7.19-7.25 (3 H, m), 6.99-7.06 (2 H, m), 6.95 (1 H, d, J=8.2 Hz), 4.89 (1 H, br. s.), 4.20 (1 H, t, 7=8.2 Hz), 3.45 (3 H} s), 2.92 (1 H, td, J=6.7, 3.1 Hz), 2.76-2.86 (1 H, m), 2.59-2.75 (2 H, m) , 2.07-2.14 (1 H, m), 0.85-0.91 (2 H, m)s 0.63-0.70 (2 H, m). Example 9 149653.doc •297- 201107311 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl )-N4-cyclobutyl-7 phenyl-6,7-diar argon-5H-cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d] mouth bite amine (165 mg, 0.55 mmol) with 4-(4-gas-1H To a mixture of -imidazol-1-yl)-3-decyloxyaniline (135 mg, 0.605 mmol) in EtOAc (EtOAc) The mixture was stirred at 97 ° C for 20 hours. After cooling to room temperature, 100 mL EtOAc was added, washed with saturated NaHC.sub.3/water and water. Purification of the residue via Biotage (12 g 'hexanes - 80%EtOAc) to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3- methoxyphenyl)-N4-cyclobutane 7-Phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (202 mg, 0.394 mmol, 71.6% yield). LC-MS (M+H)+ = 487.14. 'H NMR (500 MHz, CDC13) δ ppm 7.92 (1 H, d, /=1.8 Hz), 7.51 (1 H, d, 7=1.2 Hz), 7.28-7.33 (2 H, m), 7.18-7.24 (3 H, m), 7.13 (1 H, s), 7.03 (1 H,d, «7=8.5 Hz), 7.01 (1 H,d,J=1.2 Hz), 6.74 (1 H, dd, 7 =8.5, 2.1 Hz), 4.64-4.80 (2 H, m), 4.17-4.23 (1 H, m), 3.49 (3 H, s), 2.72-2.81 (1 H, m), 2.61-2.71 (2 H, m), 2.43-2.53 (2 H, m), 2.09 (1 H, td, /=8.0, 2.3 Hz), 1.92-2.04 (2 H, m), 1.70-1.88 (2 H, m). Example 10 149653.doc -298-201107311 N2-(4-(4-Ga-1H-imidazol-1-yl)-heptyloxyphenyl)-N4-isopropyl-7-phenyl-6,7- Dihydro-5H-cyclopenta[d] bleed 2,4-diamine

2-(Gas-N-isopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]°-biti-4-amine (154 mg, 0.535 mmol) with 4-(4) To a solution of chloro-1H-imidazol-l-yl)-3-methoxyaniline (114 mg, 0.50 mmol) in EtOAc (EtOAc) The mixture was mixed at 94 ° C for 20 hours. After cooling to room temperature, 丨 00 mL EtOAc was added and washed with saturated NaHC EtOAc. The residue was purified via EtOAc (EtOAc EtOAc) Propyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (120 mg, 0.23 mmo yield 47.2%). LC-MS (Μ+Η)+=475·2. NMR (500 MHz, CDC13) δ ppm 7.92 (1 H, d, J=2.l Hz), 7.51 (1 H, d3 J=1.5 Hz), 7.31 (2 H, d, 7=7.3 Hz), 7.22 -7.25 (2 H, m), 7.22 (1 H, s), 7.08 (1 H, s), 7.04 (1 H, d, /= 8.5 Hz), 7.01 (1 H, d, J=1.5 Hz) , 6.74 (1 H, dd, J=8.45 2.3 Hz), 4.38-4.46 (1 H, m), 4.33 (1 H, d, /=7.9 Hz), 4.18-4.24 (1 H, m), 3.49 ( 3 H, s), 2.72-2.80 (1 H, m), 2.61-2.71 (2 H, m), 2.07-2.14 (1 H, m), 1.33 (6 H, t, */= 6.6 Hz). Example 11 149653.doc •299-201107311 #-(4-(4-Chloro-1&amp; imidazol-1-yl)_3_methoxyphenyl)_7_(4-fluorophenyl)_N4-methyl-6, 7-dihydro-5H-cyclopenta[d] shouting-2,4-diamine

2-Ga-7-(4-fluorophenylmethyl-6,7-dihydro-5//-cyclopenta(4)pyrimidin-4-amine (307.5 mg, 1.107 mmol) and 4-(4-gas A solution of -li/-imidazol-1-yl)-3-methoxyaniline (248 mg, 1.107 mmol) in THF (3 mL)EtOAc (EtOAc) The solvent was wet-milled with decyl alcohol, cooled in a chiller and filtered. The precipitate was washed thoroughly with methanol and dried to give &lt;RTI ID=0.0&gt;&gt; -3 -methoxyphenyl)-7-(4-fluorophenyl)-#-methyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine (207.9 mg, 0.447 mmo yield 40.4%) 〇LC-MS (M+H)+=465.0 〇NMR (500 MHz, CDC13) δ ppm 9.18 (1Η, s), 8.15 (1H, d, 7=1.8 Hz), 7.73 (1H,d, "7=1.5 Hz), 7.41 (1H,d, "7=1.5 Hz), 7.18-7.26 (2H, m), 7.07-7.18 (2H, m), 6.88-7.00 (1H, m), 4.12-4.20 (1H, m), 4.04-4.12 (1H, br s), 3.60 (3H, s), 3.17 (1H, s), 2.96 (3H, d, 7=4.6 Hz) , 2.71-2.81 (1H, m), 2.52-2.66 (2H, m), 1.83-1.96 (1H, m).

Examples 11A and 11B (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-1^4-methyl -6,7-dihydro-511-cyclopenta[(^] mouth. -2,4-diamine 149653.doc •300· 201107311 (R)-N2-(4-(4-chloro-1H- Imidazolyl-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-#-methyl-6,7-dihydro-51{-cyclopenta[(1]pyrimidine-2&gt ;4-diamine

Purification of W2-(4-(4-chloro·1//--micron-1-yl)-3_decyloxyphenyl)-#-triterpene by palmar supercritical fluid chromatography (SFC) a racemic mixture of -7-phenyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine (150 mg, 0.206 mm〇1 'from Shih Hung 77) , get 74.6 mg peak A (real you &quot; J) and 71.7 mg peak B (f do not &quot; fi). SFC method: Chiralpak 〇JH (3〇x250 mm, 5 μΜ) '35% sterol in C02 (〇·ι〇/0 diethylamine), 35 ° C, flow rate 70 mL / min 'maintained for 12 minutes, 268 nm Absorbance, 0.75 mL of a 15 mg/mL solution in methanol (multiple stack injections), iR (peak A) = 4.0 minutes '~ (peak B) = 8.6 minutes. The absolute stereochemistry of the individual enantiomers (the actual &quot;party) was not determined. The LC-MS and 1 NMR analytical data of the separated enantiomers were identical to those of the racemic compound. Example 12 N -(3-Fluoro-4-(5-methyl-ih-1,2,4-triazol-1-yl)phenyl y7_(4-fluorophenyl)N-methyl_6,7- Dihydro-5H-cyclopenta[d] mouth bite-2,4-diamine 149653.doc 301 · 201107311

2-Chloro-7-(4-fluorophenyl)-sodium-6,7-dihydro-5-p-pentyl[d]pyrimidin-4-amine (105.0 mg, 0.378 mmol) and 3-fluoro 4-(3-mercapto-1//- 1,2,4-di-iso-1-yl)aniline (72.7 111 LV, 0.378 111111 〇1) in 1[1^(2 1111〇) 60% sodium hydride in mineral oil suspension (30.2 mg, 0.756 mmol) was added to the solution. The reaction mixture was stirred at 80 ° C for 40 minutes. The reaction mixture was further stirred at 80 ° C for 4 hours. The reaction mixture was quenched and extracted with EtOAc (EtOAc) (EtOAc m. 3_Fluor_4_(3_methyl_1/f_l2,4·triazol-1-yl)phenyl)-7-(4-fluoroindolyl_6,7-dihydro_5// _ Cyclopenta[d]. Bite 2,4-diamine di TFA salt (45 6 mg, 〇_ 咖.. ^ ^ 1 8.250/0) 〇LC-MS (M+H)+=434.0 〇 &gt;H NMR (500 MHz, TUwPpm8.86 (1H, s), 7.88 (1HtJ=84Hz) 72i_ 7·31 OH, m)s 7.19 (1H, d5 7=8.9 Hz), 7.07 (2Hj t, y= 8.7 Hz), 4.27 (1H, t5y=8.5Hz), 3.73(3H, s), 3.33 (3H, s), 2.5 2 (out, dcW=8,2,(ο Hz), 2.49 (3H,s), 2 38 (ih, &amp; wind 6

Hz), 2.30 (1H, d, "7=3.7 Hz), 1.95-2.07 (1H, m). Example 13 N2-a-fluoro-5.methoxy_4-(3-methyl-1H-12,4-triazole small)phenyl 7-(4-fluorophenyl)'methyl-6,7- Dihydro-5H-cyclopenta(4)対149653.doc •302· 201107311 Diamine

To 2-chloro-7-(4-fluorophenyl)-indole-indenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-amine (105.0 mg, 0.378 mmol) a solution of 2-fluoro-5-methoxy-4-(3-mercapto-l/fl, 2,4-triazol-1-yl)aniline (84 mg, 0.378 mmol) in THF (2 mL) A 60% sodium nitrate mineral oil suspension (9.07 mg, 〇·378 mmol) was added. The reaction mixture was stirred at 80 ° C for 40 minutes. The reaction mixture was further stirred at 80 ° C for 4 hours. The reaction mixture was quenched with aqueous ammonium chloride and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified mpqqqqqq Phenyl)-7-(4-fluorophenyl)-#-mercapto-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine di TFA salt 20.2 mg, °·027 mmol, yield 7.19%). LC-MS (1^+11)+=464.0 04 NMR (500 MHz, decyl alcohol) δ ppm 9.06 (1H, s), 7.74 (1H,d, /=10.4 Hz), 7.19-7.28 (3H, m), 7.07 (2H, t, 7=8.5 Hz), 4.24 (1H, s)5 4.00 (3H, s), 3.76 (3H, s), 2.48 (3H, s), 2.40-2.54 (1H, m ), 2.26-2.38 (2H, m), 1.89-2.02 (1H, m) ° Example 14 1^2-(6-(4-Ga-1){-Mimi-1_yl)_5_methoxy .Bistidin-3-yl)-7-(4-fluorophenyl:^-methyl-baro-dihydro-nuclear-cyclopenta(4)pyrimidine-diamine 149653.doc -303· 201107311

To 2-chloro-7-(4-fluorophenyl)-#-mercapto-6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine (165.3 mg, 0.595 mmol) Add 60% sodium hydride to a solution of 6-(4-chloro-1//-imidazol-1-yl)-5-decyloxypyridin-3-amine (134 mg, 0.595 mmol) in THF (3.5 mL) Mineral oil suspension (286 mg, 1.190 mmol). The reaction mixture was heated at 8 Torr in a capped vial for 6 hours. The reaction was quenched with aqueous ammonium chloride and the product was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by reverse-phase preparative HPLC to give the product as a brown oil -1 </ RTI> &lt;RTI ID=0.0&gt; -(4-fluorophenylmethyl-6J_dihydrogen is preferably cyclopenta[d]pyrimidine-2,4-diamine-TFA salt (2 6.2 mg '0.029 mmol, yield 4.88 %). LC-MS (M+H)+=466·0. 4 NMR (500 MHz, decyl alcohol-to) δ ppm 8.43 (!Η, s), 7.96 (1H, S), 7.87 (1H, s), 7.55 (1H, Br. s.), 7.19- 7.32 (2H, m), 7.07 (2H,t,^/=8.7 Hz), 4.20-4.29 (1H,m), 4.〇6 (3H,s),3.75 (3H , s), 2.42-2.55 (1H, m), 2.21-2.39 (2H, m), i.90_2 〇5 (1H, m). Example 15 N-(4-(4-Ga-1H_imidazole·^ Base)% f oxyphenyl)_4-(3,3-difluoroazetidin-1-yl)-7-(4-fluorophenyl)_67_dihydro_5H_cyclopenta[d] Pyrimidine 2·amine 149653.doc 201107311

2-Chloro-4-(3,3-difluoroazetidin-1-yl)_7-(4-fluorophenyl)_6,7-dihydro-5//-cyclopenta[〇1]pyrimidine (42.6 11^, 〇.125 111111〇1) and 4-(4-gas-1//-imidazole-buyl)-3-methoxyaniline (28.0 mg, 〇.125 〇1) in THF ( The solution in 1 mL) and acetic acid (1.000 mL) was heated overnight at 8 °C. Heating was continued overnight at 120 °C. After cooling, the reaction mixture was purified by hydrazine column chromatography to give a brown oil: V_(4_(4- _ _ _ _ _ η 嗤 嗤 1- yl) 3- methoxy phenyl)- 4-(3,3-difluoroazetidinyl)-7-(4-fluorophenyl)-6,7-dihydro-5/f-cyclopenta[d]pyrimidine-2-amine TFA salt (u 8 mg, 0.018 mmol, yield 14.54%). LC-MS (Μ+Η)+=527·1. 4

NMR (500 MHz, CDC13) δ ppm 11.75 (1H, s), 8.02 (1 Η, s) 7.40 (1H, dd, J=S.5, 2.1 Hz), 7.32 (1H, d, 7=2.1 Hz), 7.16- 7.23 (3H,m), 7.12 (1H, s), 7.02 (2H, t, &lt;7=8.7 Hz), 4.42 (1H, dd, /=9.5, 4.9 Hz), 4.80 (4H, s) , 3.85 (3H, s), 3. Π (1H, s), 2.98 (1H, s), 2.67-2.79 (1H, m), 2.26 (1H, d). Example 16 4-(3,3-Difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-1 bis, 4-triwa-1-yl) Phenyl)-7-(4-fluorophenyl)_6,7-dihydro-51{-cyclopenta[d]sodium-2-amine 149653.doc -305 - 201107311

Fv F

To the -chloro-'^-difluoroazetidin-bububu^-fluorophenyl)...,, a hydrogen-5H-cyclopenta[d]e-densified d subfield]) (丨7〇mg, 〇5〇〇 in THF (1498 μ! 添加 added 3_Fluor_4_(3_methyl_1H1,2,4_2. sit-1-yl) stupid amine The resulting mixture was heated to i 〇crc and stirred overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (C18, 30.times. Purification by HzO/TFA) gave 4_(3,3-dioxaazetidinyl-fluorenyl)_ν·(3_._4_(3_ 曱基·1Η_ι, 2,4-three° sitting) in the form of a beige solid _1_yl)phenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine TFA salt (racemate) (101.49 mg , yield 33.27%). LC-MS (M+H)+=496.1 〇iH NMR (500 MHz, MeOD) δ ppm 8.06-8-11 (1 H, m)^ 7 g6 (1 H&gt; dd) j =i2.51, 2.14 Hz), 7.47-7.57 (2 H, m), 7.28-7.35 (2 H, m), 7.11-7.19 (2 H, m)} 4.93 (4 H, t, J=11.90 Hz ), 4.47 (1 H, t, 7=7.93 Hz), 3.11-3.18 (1 H, m), 2.99-3.08 (j H, m), 2.71-2.81 (1 H, m, J=13.31, 8.91,8.91, 4.27 Hz), 2.42 (3 H, s), 2.08-2.19 (1 H, m, 7=13.24, 9.04, 6.71, 6.71 Hz).

Example 16A 4_(3,3-Difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-149653.doc •306· 201107311 1,2,4 -2° sitting-1-yl)benyl)-7-(4-fluorophenyl)-6&gt;7-dihydro-5 ugly-cyclopenta[d]pyrimidin-2-amine

Isolation of 4-(3,3-distribute azetidine by multiple injections of palmitic SFC (Chiracel OJ-H 30x250 mm, 5 μΜ '30°/. MeOH (0.1% DEA)/C02) 1-yl)-N-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-trisylphenyl)phenyl)7-(4-fluoro-based)-6,7-di Hydrogen - 5H-cyclopenta[d]° sessile _2_amine (purple you M) 'A 4-(3,3-difluoroazetidin-bu)-N- as an off-white solid (3-Fluoro-4·(5-mercaptotriazole-byl)phenyl)·7(4fluorophenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidin-2-amine ( First eluted, enantiomer A). LC-MS (M+H)+=496.1. 4 NMR (500 MHz, MeOD) δ ppm 7-87-8.08 (2H, m), 7.35-7.44 (1 H, m), 7.31 (1 H, t , 7=8.70 Hz), 7.24 (2 H, dd, /=8.55, 5.49 Hz), 7.04 (2 H, t, J=8.70 Hz), 4.64 (4 H, t, /=12.05 Hz), 4.19 ( 1 H, t, 7=8.24 Hz), 2.98-3.08 (1 H, m), 2.86-2.98 (1 H, m)5 2.55-2.68 (1 H, m, J=12.86, 8.60, 8.60, 4.12 Hz ), 2.37 (3 H, s), 1.97-2_12 UH, m). Not measured; f your absolute stereochemistry.

Example 16B 4_(3,3-Difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-methyl-1H-149653.doc-307-201107311 1,2,4 -triazolyl)phenyl)_7_(4-fluorophenyl)·6 &amp; [d]tongridin-2-amine

Separation of 4(33 diazetidine-1) by multiple injections of palmar SFC (Chiracel 〇J_H 3〇χ25〇_, $ μΜ' 30% MeOH ((M% DEA)/c〇2) -yl)-Ν-(3-fluoro_4_(5-mercaptotriazolyl)phenyl)-M4-fluorophenyl)·6,7-dihydro-5H_cyclopenta[d]pyrimidine_2 Amine (actual / 6) gave 4_(3,3-difluoroazetidinyl)-N-(3- -4-(5-methyl-1H-1) as an off-white solid. , 2,4-triazol-1-yl)phenyl)_7_(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (second elution, Enantiomer '--虱-5H-cyclopenta isomer B). LC-MS (M+H)+ =495. H NMR (500 MHz MeOD) δ ppm 7.96-8.09 (2 Η, m), 7.39 (ι h, dd, J=9.00, 1.98 Hz), 7.32 (1 H, t, J=8.55 Hz), 7.20-7.28 (2 H, m), 6.99-7.11 (2 H, m), 4.65 (4 H, t, */=12.21 Hz), 4.20 (1 H, t, 7=8.24 Hz), 2.99-3.09 (1 H , m), 2.88-2.99 (1 H, m), 2.56-2.71 (1 H, m), 2.31-2.46 (3 H, m), 1.98-2.15 (1 H, m). The absolute stereochemistry of the actual operation was not determined. Example 17 N-(4-(3-Chloro-1H-1,2,4-triazol-1-yl)-3-f-oxyphenyl)-4-(3,3-149653.doc-308- 201107311 -6,7-Dihydro-5}1-cyclopentafluoroazetidin-1-yl)_7_(4-fluorophenyl)[d]pyrimidin-2-amine

Fv F

2-Hydroxy-4-(3,3-difluoroazetidinyl)-7-(4-fluorophenyl)6 7-dihydro-5Η-cyclopenta[d]pyrimidine Mg, 〇5〇〇mm〇1) and 4-(3-gas-1H-1,2,4-tris-1-yl)_3·nonylaniline (food powder F) (146 mg, 〇 _650 mmol) KTHF (1498 μί) was added to the solution in 1498 μΙ〇. The resulting mixture was heated to i 〇〇 °c and mixed overnight. The reaction mixture was then concentrated in vacuo. MeOH was added to the residue to give a suspension. This suspension was transferred to give a solid which was dissolved in hot MeOH and then transferred. The mixture was then concentrated in vacuo to give a yellow solid.

&gt;^-(4-(3-Gas-111-1,2,4-triazol-1-yl)-3-decyloxyphenyl)_4-(3,3-difluoroazetidine Alkan-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (racemate) (130 mg, yield 49.22 %). LC-MS (M+H)+ = 528.1. ^ NMR (500 MHz, MeOD) δ ppm 8.81 (1 Η, s), 7.65 (1 Η, d, J=8.55 Hz), 7.59 (1 H, s), 7.29-7.36 (2 H, m), 7.11 -7.21 (3 H, m), 4.87-4.88 (4 H, m), 4.47 (1 H, s), 3.91 (3 H, s), 3.11-3.19 (1 H, m), 2.99-3.08 (1 H, m), 2.77 (1 H, dddd, /=13.47, 8.96, 4.43, 4.27 Hz), 2.13 (1 H, dq, /=8.89, 6.70 Hz). 149653.doc •309· 201107311

Example 17 A N-(4-(3-Gas-1H-1,2,4-triazol-1-yl)-3-methoxyphenyl)_4_(3 3 difluoroazetidine-1 -yl)-7-(4-fluorophenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidin-2-amine

N_(4_(3_气)H_ 1,2,4-di was isolated by multiple injections of palmitic SFC' (Chiracel AD-H 30x250 mm, 5 μΜ, 45% MeOH (0.1% DEA)/C02). -1--1-yl)-3-decyloxyphenyl)-4-(3,3-dioxoazadin-1·yl)-7-(4-fluorophenyl)-6,7- Dihydro-5H-cyclopenta[d] ° 密_2_amine (act 7 7), 4-(3,3-difluoroazetidinyl)_N_ (3) -Fluoro-4-(5-mercapto-1 Η-1,2,4-triwax-yl)phenyl)-7-(4-fluorophenyl)· 6,7-dihydro-5H- Cyclopenta[d]pyrimidin-2-amine (first eluted, enantiomer A). LC-MS (M+H)+ = 528. 1H NMR (500 MHz, Z) Λ / lS Ό -d6) δ ppm 8.82 (1 H, d, 7 = 1.53 Hz), 8.06 (lh, s), 7.35 (1 H, d, "7=8.85 Hz), 7.21. -7.31 (2 H,m),7.07-7 21 (3 h,m), 4.70 (4 H, t, J=12.36 Hz), 4.20 (1 H, t, J=8.24 Hz), 3.63 (3 H , br. s.), 3.01 (1 H, br. s·), 2.80-2.95 (1 H, m), 2.53-2.63 (1 H, m), 1.93 (1 H, d, J = 8.24 Hz) . The absolute stereochemistry of the actual operation was not determined. 149653.doc -310- 201107311

Example 17B N-(4-(3-Gas-1H-1,2,4-triazol-1-yl)-3- methoxyphenyl)-4-(3,3-difluoroazetidine Alkan-1-yl)-7-(4-fluorophenyl)-6J-dihydro-5Η-cyclopenta[d]pyrimidin-2-amine

F Enantiomer Β of Example 17 Separation of N-(4-(3) by multiple injections of palmitic SFC (Chiracel AD-H 30x250 mm, 5 μΜ, 45% MeOH (0.1% DEA)/C02) -chloro-1H- 1,2,4-oxadiazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidinyl)-7-(4- -6, 氤 ))-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (f 7 7), 4-(3,3-difluoro nitrogen heterocycle in the form of a yellow film Butane-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)_ _ 6,7- Dihydro-5H-cyclopenta[d]pyrimidin-2-amine (second elution, enantiomer B). LC-MS (M+H)+=528.1.]H NMR (5〇〇 MHz, DMSO-ds) δ ppm 8.76-8.92 (1 Η, m), 8.06 (1 Η, br. s.), 7.30-7.45 (1 H, m), 7.25 (2 H, d, J=5.49 Hz ), 7.05-7.19 (3 H, m), 4.57-4.80 (4 H, m), 4.20 (1 H, br. s.)5 3.63 (3 H, br. s.), 3.00 (1 H, br s.), 2.82-2.94 (1 H, m), 2.53-2.61 (1 H, m), 1 · 9 1 (1 H, br s.). The absolute stereochemistry of the real/i 75 is not determined. Example 18 149653.doc -311 - 201107311 • Oxygen·5_azabicyclo[221]g _5_yl)yl)m-phenyl)w-based dioxetane[d]Fixed _2_amine

According to the real (four) combination (1S, 4S) _5-(2-gas _7-(4-fluorophenyl)_6,7-dihydro 5H·cyclopenta[d(tetra)_4·yl)_2_oxindole azabicyclo[22ι Geng Shao ^ light 6) (148 mg, 0.428 mmol) and 4-(4-gas-1 Η-flavored sali-i-yl)_3 methoxyaniline (袅菜与^) (124 mg, 0.556 mm〇i And purify to give 4-((lS,4S)-2-oxo-5-azabicyclo-u 2^h-hungyl) N-(4-(4- gas-1H-imidazole) as a brown solid. 1-yl)-3-decyloxyphenyl)·7_(4_acetoyl)-6,7-diar-5-cyclopenta[d]pyrimidin-2-amine TFA salt (diastereomeric The mixture was (106 mg, 0.164 mmol' yield 38.3%). LC-MS (M+H)+= 533.1. 4 NMR (500 MHz, DMSO-A) δ ppm 7.81 (1 H, s) 7·67 (1 H, br. s.), 7.49 (1 H, s ), 7.32 (3 H,d,*7=7.93 Hz), 7.19 (2 H, t, J=8.70 Hz), 7.14 (1 H, d, 7=2.14 Hz), 5.17 (l H,br. s .), 4.74 (1 H, s), 4.34 (1 H, br. s.), 3.58-3.95 (7 H,

m), 2.89-3.39 (2 H, m), 2.55 (1 H, s), 1.97 (3 H, br. s.). Example 18A 4-((lS,4S)-2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-!^-(4-(4-gas- 149653.doc -312· 201107311

1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)indole dihydro-5H cyclopenta[d]pyrimidin-2-amine

Isolation of 4-((lS,4S)-2-oxo-5' azabicyclocycle by multiple injections of palmar SFC (OD-H 30x250 mm, 5 μΜ, 30% MeOH (0.1% DEA)/C02) [2·2·1]hept-5-yl)-indole-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl -6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidinamine (act 75) gave 4-((18,43)_2_oxy-5-azabicyclo[2.2] as a beige residue. .1]hept-5-yl)-N-(4-(4-gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-2-amine (the enantiomer A is first eluted). LC-MS (M+H)+=532_9. 4 NMR (500 MHz, MeOD) δ ppm 7 § 2 (1 H, br. s.), 7.67 (1 H, s), 7.18-7.30 (3 H, m), 7.11-7.18 (1 H, m), 6.96-7.09 (3 H, m), 5.14 (1 H, br. s.), 4.72 (1 H, br. s.), 4.18 (1 H, t, 7=8.55 Hz), 3.94-4.OI (1 H} m), 3.92 (i Hj d, /=6.41 Hz), 3.78-3.86 (1 H,m), 3.69-3.78 (1 h,m ), 3.57 (3 H, s), 3.01-3.15 (2 H, m), 2.51-2.69 (1 H, m), 184_211 (3 H, m). The absolute stereochemistry of /8/ is not determined.

Example 18B 149653.doc -313· 201107311 4-((lS,4S)-2-oxo-5-azabicyclo[2.2.1]hept-5-yl)-1 (4, (4_ gas·1H- Imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-6,7-diox_5H cyclopenta[d]pyrimidin-2-amine

Separation of 4-((lS,4S)-2-oxaza double soil by multiple injections of palmar SFC (OD-H .30x250 mm, 5 μΜ, 30% MeOH (0.1% DEA)/C02) [2.2.1]hept-5-yl)-]'^-(4-(4-gas-111-0 m "1 sitting-1-yl)-3-methoxymethan)-7-(4 -Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Real 75) - Obtained as a beige residue 4_((1S,4S)_2_Oxygen_ 5-azabicyclo[2.2.1]hept-5-yl)hista-7-(4-(4-a-111-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluoro Phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (the second is eluted as 'enantiomer B'). LC-MS (M+H)+ = 532.9. NMR (500 MHz, MeOD) δ ppm 7.20-7.31 (3 Η, m), 7.17 (1 Η, d, J=8.55 Ηζ), 7.05 (3 Η, t, "7=8.09 Ηζ), 5.17 (1 Η ,br. s.), 4.72 (1 Η, s), 4.14 (1 Η, t, 7=8.09 Hz), 3.94-4.02 (1 H, m), 3.89-3.94 (1 H, m)} 3.70- 3.85 (2 H, m), 3.50-3.68 (3 H, m), 3.20-3.31 (1 H, m)} 2.96 (1 H, ddd, J=14.65, 7.78, 7.48 Hz), 2.48-2.66 (1 H, m, /=^3 〇 8, 8.72, 8.72, 4.27 Hz), 1.89-2.11 (3 H, m). The absolute stereochemistry of 7(10) was not determined. 149653.doc -314-201107311 Example 19 N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-( 2-methylpyrrolidine a.yl)_6,7-dihydro-5H-cyclopentapyrimidine-2-amine

According to the combination of Chuanxi/Μ 2_Chloro_7_(4_fluorophenyl)_4·(2曱ylpyrrolidinyl-i-yl)_6,7-dihydro-5H_cyclopenta[d]pyrimidine (# # #HCj〇(159 mg, 0.479 mmol) and 4-(4-Gas-1H-imidazole-Im-yl)_3_decyloxyaniline (j/潆^^) (139 mg, 0.623 mmol) n~(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_7_(4fluorophenyl)_4_ (2-methylpyrrolidine-i_) as a brown solid )6,7_Dihydro-S-cyclopenta[d]pyrimidin-2.amine salt (racemate, diastereomer, mg, 〇133 mm Ql, yield 27.8 〇/〇. LC-MS (Μ+Η)+=519·1. iH NMR (500 MHz,

MeOD) δ ppm 7.80 (1 Η, s), 7.41 (1 Η, d, J=8.55 Hz), 7.30-7.37 (4 H, m), 7.21-7.32 (1 H, m), 7.17 (2 H, t, 7=8.55 Hz), 4.68 (1 H, br. s.)3 4.44 (1 H, br. s.)5 3.94-4.23 (2 H, m), 3.88 (3 H, s), 3.37 ( 3 H, s), 3.18 (1 H, s), 2.72 (1 H, br. s.), 2.U (4H, br. s.), L83 (1 H, br. s )e Relative stereochemistry.

Example 19A N-(4-(4·Chloro-1H-flavoryl)·3_νoxyphenyl)_7_(4 gas phenyl)_ 149653.doc •315· 201107311 4-(2-methylpyrrolidine -1-yl)-6,7-dihydro-5Η-cycloindolo[d]pyrimidin-2-amine

Separation of Ν-(4-(4-Ga-1Η-imidazol-1-yl)- by multiple injections of palmar SFC (〇J_h 30x250 mm, 5 μΜ, 45% MeOH (0.1% DEA)/C02) 3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methyl)pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d Pyrimidine-2-amine (real #/79) to give N-(4-(4-Ga-1H-imidazol-1-yl)_3_methoxyphenyl)-7-(4) as a brown wax -fluorophenyl)-4_(2·decylpyrrolidinyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (first dissociated from 'enantiomer A, non-pair 〇 〇. LC_ms (Μ+Η)+ = 519·1. NMR (500 MHz, MeOD) δ ppm 7.76 (1 Η, s), 7.66 (1 Η} dj J=1 53 Hz), 7.16- 7.27 (3 H, m), 7.07- 7.16 (2 H,m), 7.02 (2 H,t,/=8.85 Hz), 4.54 (1 H,t,7=5.65

Hz), 4.07 (1 H, t, J=8.24 Hz), 3.91 (1 H, dt, 7=10.45, 4.08 Hz), 3.68-3.79 (lh, m), 3.54-3.68 (3 H, m), 3.15-3.28 (1 H, m), 2.96-3.13 (1 H, m), 2.45-2.58 (1 H, m), 2.02-2.18 (2 H, m), 1.95-2.02 (1 H, m), 1.85-1.95 (1 H, m), 1.67-1.81 (1 H' m)' 1·27 (3 h, d, *7 = 6.10 Hz). The absolute stereochemistry of the real day was not determined.

Example 19B N-(4_(4-chloro, 1H•imidazolylmethoxyphenyl)7(4-fluorophenyl)·149653.doc -316-201107311 4-(2-methylpyrrolidinyl)_6J -dihydro-5H_cyclopenta[d]pyrimidine-2-amine

Separation of Ν-(4-(4-气-1Η-味唾小基)-3 by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 451⁄4 MeOH (0.1% DEA)/C02) -nonyloxyphenyl)-7-(4-fluorophenyl)-4-(2-methylindole),6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2 -Amine (Essence 79) 'Get N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4_ gas) Phenyl)-4-(2-indolyl π ratio ο. _1 _ _) _6,7-dihydro-5 Η-cyclopenta[d] mouth bite _2 amine (second dissolution, right Isomer B, diastereomer 〇. Lc% MS (M+H)+=519.1. NMR (500 MHz, MeO£&gt;) δ ppm 7 76 (1 H, d, /=1.53 Hz ), 7.65 (1 H, d, /=1.22 Hz), 7.15-7.23 (3

H,m), 7.06-7.14 (2 H,m),6.96-7.05 (2 H,m),4.48-4.57 (丄H, m), 4.05 (1 H, t, 7=8.39 Hz), 3.85- 3.94 (1 H, m)3 3 66_ 3.76 (1 H,m), 3.60 (3 H,s), 3.16-3.26 (1 H,m),2.95_3 〇8 (1 H,m),2.44-2.55 (1 H,m,J=12.78, 8.56, 8.56, 3·97 Hz) 2.01-2.14 (2 H,m), 1.94-2.01 (1 H,m),1.85-1.94 (i H m) I. 68 -1.77 (1 H,m), 1.26 (3 H,d,J=6_10 Hz). The absolute stereochemistry of the real part 7P5 was not determined. Example 20 N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4.fluorophenyl) 149653.doc -317-201107311 4-(2 -methylpyrrolidine-dihydro-5H-cyclopenta[morphopyrimidine-2-amine

2-Chloro-7-(4-fluorophenyl)-4-(2-indolylpyrrolidin-1-yl)-6,7-dihydro-5Η-cycloindolo[d]pyrimidine according to the combination (Nongken #价2) (179 mg, 539·539 mmol) and 4-(4-Ga-1H-imidazolium-1·yl)-3-decyloxyaniline (Raid #3) (157 mg, 0.701) Methyl) and purified to give N-(4-(4-H-1H-imidazol-1-yl)-3-methoxyphenyl)-7(4-fluorophenyl)-4 as a brown solid. -(2-decylpyrrolidin-1-yl)_6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidin-2-amine TFA salt (racemate, diastereomer 2) 99.55 mg, 0·157 mmol, yield 29.2%). LC-MS (Μ+Η)+=519·1. NMR (500 MHz, MeOD) δ ppm 7.80 (1 H, d, J = 1.53 Hz), 7.41-7.60 (1 H, m), 7.40 (1 H, s), 7.30-7.37 (3 H, m), 7.21-7.29 (1 H, m), 7.16 (2 H, t, J=8.70 Hz), 4.68 (1 H, br. s.), 4.45 (1 H, d5 J=7.93

Hz), 4.17 (1 H, br. s.), 4.00 (1 H, br. s.), 3.88 (3 H, s), 3.34-3.48 (2 H, m), 3.17-3.30 (1 H, m), 2.73 (1 H, br. s.), 2.11 (4 H, br. s.), 1.81 (1 H, br. s.), 1.35 (3 H, d, "/= 6.41

Hz). The relative stereochemistry of the actual rush 20 was not determined.

Example 20 A N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)· 4-(2-methyl ° ratio嘻-1-yl)-6,7-di-gas-5H-cycloindole[d] ° 唆-2-amine 149653.doc -318- 201107311

Separation by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 45% MeOH (0.1% DEA)/C02)

3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-amidopyrrolidine small group) 6,7-dihydro-5Η-cyclopenta[d] Pyrimidin-2-amine (20), obtained N-(4-(4-Ga-1H-miso-1-yl)-3-methoxyphenyl)-7- 4-fluorophenyl)-4-(2-decylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (first eluted, enantiomer Body A, diastereomer 2). LC-MS (M+H)+=519.1 = !H NMR (500 MHz, MeOD) δ ppm 7.75 (1H, d, 7=1.83 Hz), 7.65 (1 H, d, 7=1.53 Hz), 7.14 -7.22 (3 H, m), 7.05-7.14 (2 H, m), 6.96-7.05 (2 H, m), 4.55 (1 H, td, /=6.41, 2.44 Hz), 4.10 (1 H, t , J=8.39 Hz), 3.86-3.95 (1 H, m), 3.73 (1 H, dt, /=10.15, 7.74 Hz), 3.59 (3 H, s), 3.16-3.25 (1 H, m), 3.06-3.16 (1 H, m), 2.52 (1 H, dddd, J=12.70, 8.70, 8.51, 3.97 Hz), 2.02-2.16 (2 H, m), 1.82-2.02 (2 H, m), 1.65 -1.78 (1 H, m), 1.27 (3 H,d,/=6.10 Hz). The absolute stereochemistry of 2 is not determined.

Example 20B N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidine·卜基)^^ Dihydro _5Η·cyclopenta[d]pyrimidine_2-amine 149653.doc -319· 201107311

Separation of Ν-(4-(4-气-1Η-imidazole-1) by multiple injections of palmar SFC (〇j_h 3〇χ250 mm, 5 μΜ, 45°/〇 MeOH (0_l% DEA)/C02) -yl)-3-methoxyphenyl)-7-(4-fluorophenyl)_4_(2-indolyl D-pyridin-1-yl)-6,7-dihydro-5H-cyclopenta [d]pyrimidin-2-amine (actually 20) to give N-(4-(4-chloro-1H-imidazol-1-yl)_3_decyloxyphenyl)_7_(4_) as a brown wax Fluorophenyl)-4-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (first elution of 'enantiomers Bulk B 'diastereomer 2). 1^〇MS (M+H) =519.1 » *H NMR (500 MHz, MeOD) δ ppm 7.75 (1 Η, s), 7.65 (1 Η, d, /=1.53 Hz), 7.14-7.21 (3 H , m), 7.05-7.14 (2 H, m), 6.96-7.04 (2 H, m), 4.49-4.58 (1 H, m), 4.10 (1 H, t} J-8.55 Hz), 3.84-3.93 (1 H, m), 3.69-3.78 (1 H, m), 3.55-3.61 (3 H,m), 3.15-3.24 (1 H,m),3.05-3.15 (1 H,m), 2.52 (1 H, dddd, J=12.67, 8.62, 8.47, 4.12 Hz), 2.02-2.17 (2 H, m), 1.83-2.02 (2 H, m), 1.65-1.77 (1 H, m), 1.23-1.32 ( 3 H,m). The absolute stereochemistry of Violet 2 (10) was not determined. Example 21 N-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxyphenyl)_4_((2S,6R)_ 2,6--methylmorphinyl))- 7-(4-Fluorophenyl)-6,7-dihydroindole-cyclopenta[d] shouting 2-amine 149653.doc •320- 201107311

According to #合(2S,6R)-4-(2-gas-7-(4-fluorophenyl)·6,7-dihydro-5Η-cyclopenta[dh-bit _4_yl)·2, 6_Dimercaptomorpholine (glyme mg, 0.616 mmol) and 4-(4-gas-1Η-imidazolium-1-yl)_3_methoxyaniline (Nong Panyou 3) (179 mg, 0.801 mmol) And purified to give N-(4-(4- gas-1H-imidazol-1-yl)-3-methoxyphenyl)_4_((2S,6R)_ 2,6 - Sulfhydryl (N-morphinyl))-7-(4-(phenylene)-6,7-dihydro-5H-cycloindolo[d]pyrimidin-2-amine TFA salt (144 mg, 0.217 mmo) Yield 35 2%). LC-MS (M+H)+ = 549. iH miR (500 MHz, grab 0D) δ ppm 7.81 (1 Η, d, 7=1.53 Hz), 7.41 (1 H, d, J=8.55 Hz), 7.28-7.38 (4 H, m), 7.09-7.20 (3 H, m), 4.62 (2 H, br. s.), 4.45 (1 H, t, 7=7.93 Hz), 3.83-3.89 (3 H, m), 3.69-3.80 (2 H, m) , 3.25-3.30 (1 H, m), 3.13-3.23 (1 H, m), 2.94 (2 H, br. s.), 2.75 (1 H, dddd, J=13.43, 8.93, 8.77, 4.88 Hz) , 2.03-2.20 (1 H,m), 1.25 (6 H,d, "7=6.10 Hz).

Example 21A N-(4-(4-Chloro-1H•imidazolyl)·3_methoxyphenyl)_4_((2S 6R)_ 2,6-dimethyl(N_morpholinyl))_7_ (4-fluorophenyl)_6,7-dihydro·5H_cyclopenta[d]pyrimidin-2-amine 149653.doc -321 - 201107311

Separation of N_(4_(4j_1H_imidazolidinyl)-3-oxime by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 35〇/.Me〇H (0.1% DEA)/C02) Phenyl)-4-((2S,6R)-2,6-diamidino(N_morpholinyl))-7(4-fluorophenyl)-6,7-dihydro-5Η-cyclopentyl And [d]pyrimidine-2-amine (f 27), which gives a brown butterfly-like N-(4-(4- gas-1H-17m嗤-1·yl)_3·methoxyphenyl)_ 4 ((2S,6R)-2,6-monomethyl(N-morphinyl))-7-(4-fluorophenyl)_6,7-dihydro-5H-% penta[d]pyrimidine- 2-Amine (first eluted, enantiomer octa[(:_MS(Μ+Η)+=549.0 ο NMR NMR (500 MHz, MeOD) δ ppm 7.81 (1 H, d, /= 2.14 Hz ), 7.63 (1 H,d, "7=1.53 Hz), 7.11-7.20 (3 H, m), 7.08 (1 H, d, J=8.55 Hz), 6.96-7.03 (2 H, m), 6.92 (1 H, dd, 7=8.55, 2.44 Hz), 4.27-4.41 (2 H, m)5 4.08 (1 H, t, */=8-70 Hz), 3.58-3.74 (2 H, m), 3.49 (3 H, s), 2.99-3.08 (1 H, m), 2.87-2.99 (1 H, m), 2.55-2.72 (2 H, m), 2.44-2.55 (1 H, m), 1.83- 1.96 (1 H, m, "7=12.70, 8.55, 8.30, 8.30 Hz), 1 · 17_1 · 22 (6 H, m). Undetermined the absolute three-dimensionality of your 274 .

Example 21B N-(4-(4-Ga-1H-imidazol-1-yl)-t-methoxyphenyl)-4-((2S,6R)-2&gt;6-dimethyl qj-morpholinyl fluoride Phenyl)_67 • Dihydro_5H cyclopenta[d]pyrimidin-2-amine 149653.doc •322- 201107311

Separation of Ν-(4-(4-气-1Η-咪.坐-1-) by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) Benzyl-3-phenyloxyphenyl)-4-((2S,6R)-2,6-diamidino(N-morpholinyl))-7-(4-fluorophenyl)-6,7 _Dihydro-5H-cyclopenta[d]pyrimidin-2-amine (N=27/27) gives N-(4-(4-Ga-1H-imidazol-1-yl)- as a brown wax 3-methoxyphenyl)-4-((2S,6R)-2,6-diamidino(N-morpholinyl)-7-(4-fluorophenyl)-6,7-dihydro- 5H-cyclopenta[d] mouth bite-2-amine (second elution, enantiomer b). LC-MS (M+H)+=549.0 NMR (500 MHz, MeOD) δ ppm 7.81 (1 H, d, /= 2.14 Hz), 7.63 (1 H, d, J = 1.53 Hz), 7.11-7.19 (3 H, m), 7.04-7.11 (1 H, m), 6.95-7.03 (2 H, m), 6.92 (1 H,d (W=8.39, 2.29 Hz), 4.27-4.42 (2 H,m ), 4.08 (1 H, t, • 7 = 8.70 Hz), 3.59-3.73 (2 H, m), 3.49 (3 H, s), 2.98-3.08 (1 H, m), 2.88-2.98 (1 H , m), 2.55-2.70 (2 H, m), 2.43-2.55 (1 H, m), 1.79-1.97 (1 H, m, J=12.70s 8.55, 8.30, 8.30 Hz), 1 · 17-1.21 (6 H, m). Absolute stereochemistry of step f / 275 was not determined. Example 22 1-(2-(4-(4-Chloro-1H-imidazol-1-yl)-3-yloxyphenylamine) _7_(4_Phenylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidine _4-alcohol 149653.doc -323 - 201107311

PH

Combination of 1-(2-lacty-7-(4-phenylphenyl)_6,7-dihydro-5h_cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidine-4 according to shoulder 7 -Alcohol (Nongken #//e) (374 mg, 1.034 mmol) and 4-(4-chloro-1H-imidazol-1-yl)_3_methoxyaniline (袅潆 j j) (301 rag, 1.344 Ment) and purified to give 1-(2-(4-(4-)-1H-imidazol-1-yl)-3-decyloxyphenylamino)_7_(4-fluorobenzene as a yellowish solid. Base)-6,7-dihydro-5 H-cyclopenta[d]° succin-4-yl)-4-methyl brigade bite &gt; 4-alcohol (89 mg ' 0.162 mmol ' yield 15.68% ). LC-MS (M+H)+= 549.3 » A NMR (500 MHz, Ζ&gt;Μ50-α?6) δ ppm 7.82 (1 H,s), 7.64 (1 Η, br. s.)3 7.50 (1 Η, s), 7.27-7.43 (3 Η, m), 7.20 (3 Η, t, 7=8.70 Hz), 7.06 (1 H, dd, J=8.39, 1.68 Hz), 4.36 (3 H, br. s.), 3.73 (3 H, br. s.), 2.98-3.26 (3 H, m), 2.59 (1 H, br. s.), 1.88-2.06 (1 H, m), 1.62 (4 H , br. s.), 1.25 (2 H, br. s.), 1.19 (3 H, s).

Example U N-(4-(4-Gas-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethyl. Bilo-1-yl)-7-( 4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine 149653.doc - 324 - 201107311

According to the actual eve; / 7 (5 combination 2-gas-4-(2-ethyl. than slightly bite-1 -yl)_7-(4-phenylphenyl)-6,7-dihydro-5H-cyclo Pentative [d]pyrimidine (Nongken #////) (77 mg, 0.223 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Nongpan powder 3 (64.7 mg '0.289 mmol) and purified to give (4-(4-chloro·1Η-味&quot;sodium-1-yl)-3-decyloxyphenyl)-4-( 2-ethyl" than slightly 唆 1- 1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5 fluorene-cyclopenta[d]pyridin-2-amine TFA salt (examination Spiral 'diastereomer 1) (53.3 1 mg, 0.082. mmol, yield 37.0%). LC-MS (M+H)+=533.3. NMR (500 MHz,

MeOD) δ ppm 7.79 (1 Η, br. s.)5 7.36-7.61 (2 H, m)} 7.34 (3 H,br. s·), 7.17 (3 H,br. s·),4.44 (2 H, br. s·), 4.00 (2 Η, br. s.), 3.88 (3 H, br. s.), 3.16-3.27 (1 H, m), 2.73 (2 H, br. s_), 2.09 (5 H, br· s·), 1.32 (2 H, br. s.), 0.93 (3 H, br. s.). The relative stereochemistry of cf/23 was not determined.

Example 23 A N-(4-(4-Chloro-1H-imidazol-1-yl)_3-methoxyphenyl) 4-(2-ethylpyhad-1-yl)-7-(4- Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine 149653.doc •325 · 201107311

Separation of Ν-(4-(4-Ga-1Η-imidazol-1-yl) by multiple injections of palmitic SFC (OJ-H 30x250 mm, 5 μΜ, 45% MeOH (0.1% DEA)/C02) -3-decyloxyphenyl)-4-(2-ethyl.pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5Η-cyclopenta[ d]pyrimidin-2-amine (not 23) afforded N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4- 2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (dissolved first, enantiomer) Structure A). LC-MS (Μ+Η)+=533·3. NMR (500 MHz, MeOD) δ ppm 7.60-7.70 (2 Η, m), 7.17-7.26 (4 Η, m), 7.14 (1 Η, d, 7=8.55 Hz), 6.98-7.07 (2 H, m ), 4.26-4.36 (1 H, m), 4.09 (1 H, t, J=8.24 Hz), 3.83-3.92 (1 H, m), 3.70-3.79 (1 H, m), 3.63 (3 H, s), 3.15-3.25 (1 H, m), 3.04 (1 H, ddd, 7=14.80, 7.63, 7.48 Hz), 2.48-2.60 (1 H, m, 7=12.86, 8.60, 8.60, 4.12 Hz) , 1.76-2.12 (6 H, m), 1.40- 1.53 (1 H, m), 0.94-1.00 (3 H, m). Undetermined 1 Your absolute 234 stereochemistry.

Example 23B N-(4-(4-Ga-1H-imidazolium-yl)-, methoxyphenyl)_4_(2-ethylpyridinium-1-butyryl)-7-(4-fluoro Phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine_2_amine 149653.doc •326 · 201107311

Separation of Ν-(4-(4-气-1Η-啤酒基)-3-甲 by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ 45% MeOH (0.1% DEA)/C02) Oxyphenyl)-4_(2-ethyloxaridin-1-yl)_7_(4-fluoroindol) 6,7-dihydro-5indole-cyclopenta[d]pyrimidin-2-amine Hungarian 23), obtained as a brown, N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethyl. Pyridin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (second elution, enantiomer B ). LC-MS (M+H)+ = 533. 'H NMR (500 MHz, MeOD) δ ppm 7.60-7.70 (2 H, m), 7.18-7.27 (4 H, m), 7.14 (1 H, d, 7=8.55 Hz), 7.03 (2 H, t , J-8.70 Hz), 4.31 (1 H, br. s.), 4.04-4.13 (1 H, m), 3.81-3.91 (1 H, m), 3.70-3.80 (1 H, m), 3.63 ( 3 H, s), 3.16-3.26 (1 H, m), 3.05 (1 H, ddd, 7=14.65, 7.78, 7.48 Hz), 2.54 (1 H, dddd, /=12.78, 8.70, 8.58, 4.12 Hz ), 1.76-2.14 (6 H, m), 1·41-1_54 (1 h, m), 0.97 (3 H, t, J = 7.32 Hz). The absolute stereochemistry of 235 is not determined. Example 24 N-(4-(4-Chloroimidazole-^ylbuprotyloxyphenyl)_4_(2-ethyl.Bilobit-1-yl)-7-(4-fluorophenyl)-6 ,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine 149653.doc -327- 201107311

According to the real (10) combination 2-gas_4·(2_ethyl 対 小 small base) _7 (4_ 笨 基 base) 6'7--gas _5H-% pentame (4) pyrimidine (10) teach you mg, 〇 231

Mm 丨) and 4·(4_gas_1H•imidazole·丨_yl)_3 methoxyaniline (agricultural mg, 0.301 mm〇i) and purified to give a brown solid N_(4_(4· Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_4_(2-ethylpyrrolidyl)- 7-(4-fluorophenyl)-6,7-dihydro-5Η - cyclopenta[d]&quot; succinyl-2-amine TFA salt (racemic 'diastereomer 2) (39.54 mg, 0.061 mmol, yield 26.4 〇/〇) 〇LC.MS (m +H)+=533.3 〇*H NMR (500 MHz, MeOD) δ PPm 7.78 (1 H, s), 7.28-7.44 (5 H, m), 7.17 (3 H, t, ^=8.09 Hz), 4.46 (2 H, br. s.), 4.00 (2 H, br. s.), 3.88 (3 H,

s), 3*37 (1 H, br. s.), 2.73 (2 H, br· s.), 2.09 (6 H, d, J = 4.27 Hz) ' 1.27-1.73 (1 H, m), 0.87 (3 H, br· s.). The relative stereochemistry of the purple plant was not determined.

Example 2 4 A &lt;-1-yl)-7-(4.fluorophenyl)-6,7-dihydro-51{-cyclopenta[(1]pyrimidin-2-amine

H9653.doc -328- 201107311

Separation of Ν-(4-(4-chloro-1Η-imidazole-1-) by multiple injections of palmitic SFC (OJ-H 30x250 mm ' 5 μΜ, 45% MeOH (0.1°/.DEA)/C02) Benzyl-3-phenyloxyphenyl)-4-(2-ethyln-pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5-indole And [d]pyrimidin-2-amine (Shen Hung 24) gave N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4 as a brown oil -(2-ethyl.pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (dissolved first) , enantiomer A). LC-MS (M+H)+=533.3. 4 NMR (500 MHz, MeOD) δ ppm 7.58-7.71 (2H, m), 7.16-7.26 (4 H, m), 7.10-7.16 (1 H, m ), 6.97-7.08 (2 H, m), 4.29-4.39 (1 H, m), 4.14 (1 H, t, 7=8.39 Hz), 3.82-3.93 (1 Hs m), 3.72-3.82 (1 h , m), 3.61 (3 H, s), 3.17-3.26 (1 H, m), 3.12 (1 H, ddd, J=14.80, 7.63, 7.48 Hz), 2.56 (1 H, dddd, /=12.70, 8.70j 8.51, 3.97 Hz), 1.79-2.09 (6 H, m), 1.40-1.56 (1 H, m), 〇.97 (3 H, t, &gt; 7 32 Hz). Absolute stereochemistry not measured. Example 24Β

Ν·(4·(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethyl.Bilobit-1-one)-7-(4_ Fluorophenyl)_6,7-dihydro·5Ηcyclopenta(4)pyrimidine_2_amine CI

N-(4-(4-gas-1H-) was isolated by multiple injections of palmar SFC (OJ-H 30x250 mm μΜ 149653.doc -329- 201107311 45% MeOH (0.1% DEA)/C〇2) Imidazolyl-1-yl)-3-methoxyphenyl)-4-(2-ethyl-ratio 0-decyl-1-yl)-7-(4-n-phenyl)-6,7-di Hydrogen-5Η-cyclopenta[d]pyrimidin-2-amine (not 24) gives N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxy in the form of a brown oil Phenyl)-4-(2-ethylpyrrole '3-1-yl)-7-(4-|(1phenyl)-6,7-dihydro-511-cyclopenta[(1) '&gt;Methyl 11-2-amine (second elution, enantiomer B). LC-MS (M+H)+=533.3.H NMR (500 MHz, MeOD) δ ppm 7.59- 7.70 (2 Η, m), 7.16-7.27 (4 Η, m), 7.11-7.16 (1 Η, m), 7.03 (2 Η, t, /=8.70 Hz), 4.29-4.37 (1 H, m) , 4.09-4.18 (1 H, m), 3.83-3.92 (1 H, m), 3.73-3.81 (1 H, m), 3.61 (3 H, s), 3.16-3.27 (1 H, m), 3.06 -3.16 (1 H, m), 2.50-2.61 (1 H, m, J-12.74, 8.58, 8 58 3 97

Hz), 1.80-2.10 (6 H, m), 1.42-1.55 (1 H, m), 〇·97 (3 h t &gt;/=7·48 Hz). The absolute stereochemistry of f was not determined. Example 25 4-(4-Amino-4-methylpiperidinyl)_N_(4_(4_----H-imidazolyl) 3-methoxyphenyl)-7-(4-oxophenyl) -6,7-dihydro_chuan_cyclopenta (4) biting _ Ί-amine

According to the real / / / Μ combination 1- (2 · gas-7-(4-fluorophenyl)_6,7 · dihydro _ 5 Η - cyclopentane 149653.doc • 330- 201107311 and [d] pyrimidin-4-yl -4-mercaptopipridin-4-ylamino decanoic acid terpene vinegar (Nongxele // g) (363 mg ' 0.787 mmol) and 4-(4-gas-1H-imidazolyl)_3 A Oxyaniline (Nongshou Le J) (229 mg, 1.024 mmol) and purified to give 4-(4-amino-4-indolyl-l-yl)-N-(4_(4) as a yellowish solid -chloro·1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H·cyclopenta[d]pyrimidin-2- Amine TFA salt (66.5 mg, 0.100 mmol, yield 12.76%). LC-MS (M+H)+=548.2. 4 NMR (500 MHz, φ^eOD) δ ppm 7.82 (1 H, d, /= 2.14 Hz), 7.68 (1 H, s), 7.20- 7.27 (3 H, m), 7.17 (1 H, d, /=8.55 Hz), 7.00-7.09 (3 H, m), 4.15-4.33 (4 H, m), 3.58 (3 H, s), 3.44-3.56 ( 2 H, m), 3.02- 3.21 (2 H, m), 2.61 (1 H, dd, 7=8.55, 4.27 Hz), 2.01 (1 H, dd, /=12.51, 8.24 Hz), 1.81-1.91 ( 4 H, m), 1.38-1.48 (2 H, m). Example 26 Ν2-(3·Fluoro-4_(5-methyltriazol-1-yl)phenyl)-7-(4-fluorobenzene

-) 4-methyl-6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-diamine

To 2-chloro-7-(4-fluorophenyl)_N_indolyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Add 3-fluoro-4-(5-methyl-111-1,2, to a solution of _4_amine (袅涝,///〇(144 mg, 0.518 mmol) in dioxane (2469 μΕ) 4-triazol-1-yl)benzene 149653.doc -331 - 201107311 Amine (Agriculture/Pan Powder C) (100 mg, 0.5 1 8 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (23.74 Mg, 0.026 mmol), 9,9-dimercapto-4,5-bis(diphenylphosphino)dipyridyl (30.0 mg, 0.052 mmol), Na2CO3 (82 mg, 0.778 mmol) and water ( 494 μί. The resulting mixture was heated to 110 ° C and stirred overnight. The reaction was then diluted with water (10 mL) and EtOAc (3 EtOAc) Drying through <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTI ID=0.0></RTI> <RTIgt; , 2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)_n4-indolyl-6,7-dioxin-5H-cyclopenta[d] 4-Diamine TFA salt (17 mg, 0.311 mmol, yield 59.9%). LC-MS (M+H)+=434.2. NMR (500 MHz, CDC13) δ ppm 8.06 (1 H, s), 7.96 (1 H, dd, /=12.51, 2.14 Hz), 7.48-7.59 (2 H, m), 7.26-7.33 (2 H, m), 7.09-7.18 (2 H, m), 4.46-4.54 (1 H, m), 3.17 (3 H, s), 2.87-2.97 (1 H, m), 2.74 2.85 (2 H,m), 2.40 (3 H,s), 2.09-2.21 (1 H,m).

Example 26 A N2-(3-Fluoro-4-(5-methyl-triazol-bu)phenyl)7-(4-fluorophenyl)-N4-methyl-6,7-dihydro·5H_ Cyclopenta(4)pyrimidine-24 diamine

By multiple preparative HPLC injections (OJ-H 3〇x25〇 mm, 10

149653.doc 201107311 1-yl)phenyl)-7-(4-fluorophenyl)-N4-indolyl-6,7-dihydro-5H-cyclopenta[d] ° sessile-2,4- Diamine (not 26), which gives n2_(3_fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)_7_(4_) as a transparent colorless glass Fluorophenyl)_n4_

Methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine TFA salt (first enantiomer &apos; enantiomer A). LC-MS (M+H)+ = 434.2.丨H NMR (500 MHz, MeOD) δ ppm 8.03-8.13 (2 Η, m), 7.41-7.47 (2 Η, m), 7.23-7.30 (2 Η, m)5 7.04-7.14 (2 Η, m) , 4.33 (1 Η, t, ^=7.93 Hz), 3.12 (3 H, s), 2.81-2.92 (1 H, m), 2.67-2.81 (2 H, m), 2·40 (3 H, s ). Not determined; absolute stereochemistry. Example 26B N2-(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4-methyl -6,7-dihydro-5H-cyclopenta[d] mouth bite-2,4-diamine

Separation of N2-(3-fluoro-4-(5- fluorenyl-1H-1,2,4-) by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ ' EtOH/heptane) Triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d] °°°-2,4- Diamine (f ̄ ̄ / 26) 'is obtained as a transparent colorless glass of n2-(3-fluoro-4-(5-mercapto-1H-1,2,4-trian-1-yl)phenyl)- 7-(4-Fluorophenyl)-N4·methyl-6,7·dihydro-5H-cyclopenta[d]pyrimidine·2,4-diamine TFA salt (second elution, enantiomeric Structure Β). LC-MS (Μ+Η)+=434.2. 4 NMR (500 MHz, MeOD) δ ppm 8.03-8.10 (2 H, m), 7.43-7.48 (2 149653.doc -333 - 201107311 H, m), 7.24 -7.30 (2 Η, m), 7.06-7.14 (2 Η, m)5 4.37 (1 Η, t, J-7.78 Hz), 3.14 (3 H, s), 2.83-2.92 (1 H, m), 2.69-2.80 (2 H,m), 2.40 (3 H,s), 2.05-2,16 (1 H,m). Absolute stereochemistry of the real part was not determined. Example 27 1-(2_(4-(4-Chloro-1H-miso-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl) -6,7-dihydro-5H-cyclopenta[d]pyrimidinyl)·3_(trifluoromethyl)pyrazine-3-ol

According to the combination of 1 -(2-qi-7·(4-1phenyl)·6,7-dihydro-5Ηcyclopenta[d] shouting 4-yl)-3-(trimethyl sulfhydryl) ) 吼洛 π定_3·Alcohol (Nong XieXinXun) (245 mg '0.610 mmol) and 4-(4-Ga-1H-imidazol-1-yl)_3_methoxyaniline (Nongken #乂) (177 mg '0.793 mmol) and purified to give 1-(2-(4-(4- gas-1H-i-s-s-l-yl))-3-yloxyphenylamino) as a clear, colorless glass. 7·(4-Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]. Methoxy-4-yl)-3-(3-trimethyl)pyrrolidin-3-ol TFA salt (First eluted, diastereomeric oxime) (51·4 mg '0.073 mmol). LC-MS (Μ+Η)+=589·1. NMR (500 MHz, MeOD) δ ppm 7.97 (1 H, s), 7.67 (1 H, s), 7.17-7.26 (3 Η, m), 7.14 (1 Η, d, 7=8.55 Hz), 7.04 ( 2 H, t, J=8.70 Hz), 6.91 (1 H, d, J=8.55 Hz), 4.14 (2 H, t, 7=8.85 Hz), 149653.doc -334- 201107311 3.93-4.06 (3 H , m), 3.58-3.68 (3 Η, m), 3.21-3.31 (1 Η, m), 3.09-3.21 (1 Η, m), 2.51-2.63 (1 Η, m), 2.28-2.41 (1 Η , m), 2.16 (1 Η, dd, 7=12.82, 6.41 Hz), 1.95 (1 H, dq, 7=12.82, 8.5 5 Hz). The relative stereochemistry of your 27 has not been determined.

Example 27 A 1-(2-(4-(4-Ga-1H-imi-a)-yl-3-methoxyphenylamino) 7-(4-phenylphenyl)-6,7-dihydro- 5Η·cyclopenta[d]pyrimidin-4-yl)·3 (trifluoromethyl)pyridinium

Indole-3-ol

By multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ,

45% MeOH (0.1% DEA) / CO 2 ) to isolate 1-(2-(4-(4-carbo-indolyl-1-yl)-3-decyloxyphenylamino)-7-( 4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyroo-4-yl)-3-(trifluoromethyl)° than bite-3-ol (practice / 2), 1-(2-(4-(4-chloro-1Η-β米°坐-1·yl)_3_methoxybenzylamino)-7-(4-fluoro) is obtained in the form of opaque glass. Phenyl)-6,7-dihydro-5 fluorene-cyclopenta[d] η _4_ yl)-3-(trifluoromethyl) hydrazine. Dine-3-ol (first eluted, enantiomer A) (11.34 mg, 0.019 mmol). LC-MS (M+H)+ = 589.1. Not measured: absolute stereochemistry. Example 28 1-(2-(4-(4-Chloro-1H-flavor)-1-yloxyphenylamino-fluoro 149653.doc -335·201107311 Phenyl)-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl = [difluoromethyl)吼σ each bite-3-ol

According to the combination of Μ Μ 1- 1-(2-gas-7-(4-fluorophenyl)_6 7 _ t 吸公 ' '-hydro-5H_cyclopenta(4)(tetra)-4_yl)-3-(three chyle Base_each bite_3. Alcohol (attack 劈) (245 mg '0.610 mmol) and 4-(4-chloro-1H-imidazole-i-yl)_3 methoxyaniline (袅潆我M) ( 177 mg , 0.793 mmol) and purified to give 1-(2-(4-(4·h-1H-imidazol-1-yl)-3-decyloxyphenylamino)-7-(4-benzenebenzene as a white solid. Base)-6,7-dihydro-5H-cyclopenta[d]mouthate-4-yl)_3-(trimethylmethyl group 嘻°--3-ol TFA salt (second dissolving, non- Enantiomer 2) (5 1.1 mg '0.073 mmol). LC-MS (Μ+Η)+=589·1. 4 NMR (500 MHz, MeOD) δ ppm 7.96 (1 Η, d, J=1.83 Hz), 7.68 (1 H, d, /=1.53 Hz), 7.19-7.27 (3 H, m), 7.15 (1 H, d, J=8.55 Hz), 7.04 (2 H, t, 7=8.70 Hz ), 6.95 (1 H, dd, J=8.55, 2.14 Hz), 4.10-4.21 (2 H, m), 3.95-4.04 (3 H, m), 3.61-3.69 (3 H, m), 3.27-3.32 (1 H, m), 3.08-3.20 (1 H, m), 2.57 (1 H, dddd, /=13.16, 8.74, 8.62, 4.58 Hz), 2.37 (1 H, dt, /=12.89, 9.88 Hz) , 2.18 (1 H, dd, J=12.82, 6.41 Hz), 1.93-2.05 (1 H, m) 〇 not measured actual 1 Stereochemistry.

Example 28 A 149653.doc -336· 201107311 1-(2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)_7_(heart phenyl)-6 , 7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl). ratio. Each bite-3-ol

Isolation of 1-(2-(4-(4-气-1Η-咪) by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 45°/. MeOH (0.1% DEA)/C02) Sit. 1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5-indole-cyclopenta[(1]°°° -4-yl)-3-(trifluoromethyl) ° pirate-3-ol (f s / 25), which gives 1-(2-(4-(4-)-1H- as opaque glass Imidazol-1-yl)-3-decyloxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidinyl-3- (Trifluoromethyl) piroxy-3-ol (first eluted, enantiomer A) (17.18 g, 29.2 mmol). LC-MS (Μ+Η)+=589·1. Absolute stereochemistry of eve. Example 29 N-(4-(4-Chloro-1H-miso.sodium-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)pyrrole Pyridin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-SH-cyclopenta[d]. dimethyl-2-amine 149653.doc -337- 201107311

According to the combination of the two, 1-(2-gas-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N,N-diindole Pyridoxine_3_amine (agricultural play) (ι〇9 mg, 0.302 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Nongguang #d) (67.6 mg, 0.302 mmol) and purified to give N-(4-(4-H-1H-imidazol-1-yl)-3-decyloxyphenyl)-4- 3-(Dimethylamino)pyrrolidinium-fluorenyl-(^)-fluorophenyl)_6,7-dihydro-5^cyclopenta[d]p dense. D-2-amine TFA salt (88 mg, 0.133 mmol, yield 44.0%). LC-MS (M+H)+ = 548.3.咕NMR (500 MHz, MeOD) δ ppm 7.79 (1 H, s), 7.38-7.44 (2 H, m), 7.29-7.36 (3 H, m), 7.24-7.29 (1 H, m), 7.11 7.19 (2 H,m), 4.39-4.51 (2 H,m), 4.28 (1 H,br. s.),4.05-4.17 (2 H,m),4.00 (1 H,d,/=2.44 Hz ), 3·86 (3 H, s), 3.22-3.47 (2 H, m), 3.02 (3 H, s), 2.76 (1 h, br. s.), 2.60 (1 H, br. s. ), 2.39 (1 H, br. s.) 5 2.13 (1 H} br. s.).

Example 29 A N-(4-(4-Ga-1H-imidazole q•yl)·3•methoxyphenyl)_4_(3-(dimethylamino)pyrrolidin-1-yl)-7-(4 -fluorophenyl)-6,7·dihydro-SH-cyclopenta[d] spray-decreasing Ί-amine 149653.doc - 338 · 201107311

First, N-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxy group was isolated by multiple injections of palmitic HPLC (OJ-H 30x250 mm, 30% EtOH/heptane). Phenyl)-4-(3-(didecylamino)pyrrolidine a•yl)-7_(4-fluorophenyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (No 29), N-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(3-(didecylamino)npyrrolidine was obtained. • _7_(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (first dissociated from the 'diastereomer A), followed by Secondary palmitic SFc injection (IB 30x250 mm &gt; 5 μΜ » 35% 50:50 MeOH: MeCN/(0.1% DEA) C〇2) to separate 'to obtain a transparent colorless glassy ν·(4-(4 -chloro-1H-isoazol-1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino)n-pyridyl-!-yl)_7_(4-fluorophenyl) -6,7-Dihydro-5 fluorene-cyclopenta[d]pyrimidin-2-amine (first dissociated from 'enantiomer A). LC-MS (Μ+Η)+=548·3. NMR ( 500 MHz, MeOD) δ ppm 7.83 (1 Η, d, J=2.14 Hz), 7.67 (1 H, d, J=1.22 Hz), 7.18-7.26 (3 H, m), 7.15 (1 H, d, J=8.55 Hz), 7.00-7.10 (3 H, m), 4.00-4.16 (3 H, m), 3.69-3.8 0 (1 H, m), 3.58-3.66 (3 H, m), 3.52 (1 H, t5 J=9.31 Hz), 3.26-3.31 (1 H, m), 3.06-3.17 (1 H, m), 2.83-2.94 (1 H, m), 2.49-2.61 (1 H, m, 7=13.08, 8.64, 8.64, 4.43 Hz), 2.35 (6 H, s), 2.21- 2.30 (1 H, m), 1.83 -2.03 (2 H,m), 1.33-1.41 (1 H,m). 149653.doc •339· 201107311 Determination of the absolute stereochemistry of the disease. Example 29Β Ν-(4-(4-Ga-1Η-imidazole) -1-yl)-3-methoxyphenyl)-4-(3-(dimethylamino) σ, butyl-1-yl)-7-(4-fluorophenyl)-6,7- Dihydro-5 Η-cyclopenta[d]v 吱-2-amine 0

First, N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyl was isolated by multiple injections of palmitic HPLC (OJ-H 30x250 mm, 30% EtOH/heptane). Phenyl)-4_(3-(didecylamino)pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Real score / 29) gave N-(4_(4- gas·1Η-imidazol-1-yl)-3-decyloxyphenyl)-4-(3-(didecylamino).pyrrolidine 1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidin-2-amine (first dissociated from 'diastereomer A), This was followed by multiple injections of palmar SFC (IB 30x250 mm » 5 μΜ &gt; 35% 50:50 MeOH: MeCN/(0.1°/〇DEA) C02) to give a N-( 4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3-(didecylamino)-pyrrolidin-1-yl)-7-(4 -fluorophenyl)-6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidin-2-amine (second cleavage, enantiomer B). LC-MS (M+H)+ = 548.3. NMR (500 MHz, MeOD) δ ppm 7.85 (1 Η, d, 7=2.14 Hz), Ί.61 (1 H, d, 149653.doc -340- 201107311 wind 53Hz), 7.17_7.24(3H,m 7i27 7.08 (3 H,m), 3.99-4.18 (3 η, m),3 68 3 7 01)' 6·99 (3 H,s), 3.48-3.56 (1 H, m),3.21- 3.30 (1 H , m), 3.58 (1 H, m), 2.81-2.94 (1 H, m), 2.49_2.62 (1 H' call, 3·10·3·21 s), 2.21-2.31 ( 1 H,m),1.82].99 ,called, 2.36 (6 H, absolute stereochemistry. (2H'm) ° not determined (four) eagle example 30

N-(4-(4-chloro-1H-imidazolium-fluorenyl)_3·roxy group)-7~(

Methylpiperazine small group)-6&gt;7-dihydro [native base bis 5H-pectoro[d]pyrimidin-2-amine

According to (4) the combination of 2_ gas winter (4) fluorophenyl M-(4-methyl-small-small base) · 6,7-dihydro-5H-cyclopenta[d] « close bite (agricultural collapse #价) ( 1〇9 mg, 〇314 mmol) and 4-(4-gas-1H-mi-s-yl-1-yl)-3-methoxyaniline (Growery 4 (70.3 mg, 0.314 mmol)) N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4) -methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine TFA salt (1〇4 mg, 0.160 mmo yield 51.1%) °LC- MS (M+H)+= 534.3. NMR (500 MHz, MeOZ)) δ ppm 7.79 (1 H, s), 7.52 (1 H, s), 7.26-7.36 (4 H, m), 7.08-7.16 ( 3 H, m), 4.41 149653.doc • 341 - 201107311 (1 H, t, J=8.09 Hz), 3.73 (3 H, s), 3.37-3.63 (7 H, m), 3.09- 3.28 (3 H , m), 2.97-3.03 (3 H, m), 2.67-2.79 (1 H, m)5 2.05-2.20 (1 H,m) »

Example 30A N-(4-(4-Chloro-1H-imidazolyl)_3.methoxyphenyl)-7-(4-fluorophenyl)- 4-(4-f-piperazine~1-yl)_6&gt; _Dihydro-5n_cyclopenta[d]pyrimidine-2-amine

Separation of Ν·(4_(4-Ga-1H-imidazol-1-yl)-3- by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ ' 30% EtOH/heptane) Methoxyphenyl)-7-(4-fluorophenyl)-4-(4-indolylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2 -amine (City/30), N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4) -fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine TFA salt (dissolved first, enantiomer a a) (21.6 mg, 0.033 mmol) 〇LC-MS (Μ+Η)+=534.3 〇]Η NMR (500 MHz, MeOD) δ ppm 7.77 (1 Η, br. s.), 7.69 (1 Η ,s), 7.23-7.31 (3 Η,m), 7.21 (1 Η, d, /=8.55 Hz), 6.99-7.15 (3 Η, m), 4.27 (1 Η, t, •7=8.39 Ηζ) , 3.61-3.78 (1 Η, m), 3.56 (3 Η, s), 3.38-3.53 (3 Η, m), 3.23-3.38 (5 Η, m), 3.03-3.21 (2 Η, m), 2.98 (3 Η, s), 2.67 (1 Η, dt, J=8.47, 4.16 Ηζ), 1.99-2.13 (1 Η, m). Not 149653.doc •342· 201107311 Determine your absolute stereochemistry. Example N-(4-(4-chloro-1H-imidazol-1-ylmethoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

N-(4-(4-Ga-1H-imidazol-1-yl)-3 was isolated by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ, 30% EtOH/heptane) -Methoxyphenyl)-7-(4-fluorophenyl).4-(4-methyl&gt;»asazin-1-yl)-6,7-dihydro-5H-cyclopenta[d Pyrimidine-2-amine (not 30), N-(4-(4-nitro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7 was obtained as a separable brown glass -(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine TFA salt (second Evacuation, enantiomer B) (21.6 mg, 0.033 mmol). LC-MS (M+H)+ = 534.3. NMR (500 MHz, MeOD) δ ppm 7.81 (1 H, d, /= 2.14 Hz), 7.68 (1 H, d, "7 = 1.53 Hz), 7.22-7.29 (3 H, m) 5 7.16-7.21 ( 1 H, m), 7.00-7.11 (3 H, m), 4.24 (1 H, t, J=8.55 Hz), 3.57-3.70 (1 H, m), 3.53 (3 H, s), 3.46 (3 H, br. s.), 3.27-3.36 (5 H, m), 3.02-3.18 (2 H, m), 2.98 (3 H, s), 2.60-2.72 (1 H, m), 2.00-2.10 ( 1 H, m). The absolute stereochemistry is not determined. Example η 149653.doc -343· 201107311 N-(4-(4-Gas-1H-imidon-1-yl), s 4-(piperazin-1-yl)-6,7-dimethoxybenzene Base)-7-(4-fluorophenyl)-hydrocyclopenta[morphopyrimidine-2-amine

Intermediate 3 1 -1 4-(2-(4-(4-气露味小基基)_3_methoxyphenylamino)-7(4-phenylphenyl)-6,7-dihydro- 5H-cyclopenta[d]t-determination _4_yl)

According to: T%% combination 4-(2-gas-7-(4-fluorophenyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine_ι_decanoic acid Third butyl ester (Nong Cai #///) (117 mg, 0.270 mmol) and 4-(4-Ga-1H-imidazol-1-yl)_3·methoxyaniline (Raid #4) (60.4 mg , 0.270 mmol), obtained as crude 4_(2弋4(4·chloro-1H-imidazol-1-yl)-3-decyloxyphenylamino)_7_(4-fluorophenyl)_6, 7. Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrazine-1-decanoic acid tert-butyl ester (1〇4 mg, 0.168 mmo yield 62.1%). LC-MS (M+H)+ = 620.4. 149653.doc •344· 201107311 Example u

To 4-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro -5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-decanoic acid second butyl (Huijia #3 plant 7) (167 mg, 0.270 mmol) in DCM (5 mL) TFA (500 pL, 6.49 mmol) was added to the trough. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. By preparative HPLC (Waters Sunfire C18, 50x250 .mm, Me0H/H20/TFA)

Purification afforded N-(4-(4- gas-1H-imidazol-1yl)-3-yloxyphenyl)-7-(4-phenylphenyl)-4-. Pyrazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]»-branched 2-amine TFA salt (39 mg, 0.062 mmol, yield 22.78%). LC-MS (Μ+Η)+=520·3.咕NMR (500 MHz, her OD) δ ppm 7·83 (1 H, br. s.), 7.28-7.46 (5 H, m), 7.08-7.21 (3 H, m), 4.41-4.53 (1 H , m), 4.18-4.28 (4 H, m), 3.80 (3 H, s), 3.44 (5 H, d, /= 4.27 Hz), 3.24-3.31 (1 H, m), 3.12-3.23 (1 H, m), 2.69-2.82 (1 H, m), 2.06-2.22 (1 H, m). Example n N-(4-(4-Chloro-1H-imidazol-1-yl)-3-yl-l-phenyl)-7-(4-fluorophenyl) 4-(3-(methylamino) bite — Dihydro-5Η·cyclopenta[d]pyrimidine

149653.doc -345 - 201107311 Intermediate 32-1 1-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenylamino)-7-(4- Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)aminocarboxylic acid tert-butyl ester

According to the combination of Shihsong 26, 1-(2-qi-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-yl ( Tert-butyl)aminobutyl decanoate (Nongmu//m) (148 mg, 0.331 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-decyloxybenzamine ( N. (74.1 mg, 0.331 mmol) gave crude 1_(2_(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenylamino)-7-(4 -fluorophenyl)_6'7-dihydro-5H-cyclopenta[d] whistle-4-yl) "Biabutine _3_yl (decyl) amino decanoic acid tert-butyl ester ( 104 mg, 〇·1 64 mmol, yield 49.5%), which was used without further purification. LC-MS (M+H)+ = 634.4. Example 32 According to the actual #/37, 1-(2-(4-(4-气-1H-imidazole_1_yl))3

0.331 mm〇l)Removal of the protecting group and purification, i (intermediate 32-1) (210 mg, obtained as a brown oil N_(4_ 149653.doc -346· 201107311 (4 - gas-1H-W m 0 -1-1 -yl)-3-decyloxyphenyl)-7-(4-disorganophenyl)-4-(3-(decylamino)pyrrolidin-1-yl)-6,7-dihydro -5H-cycloindolo[d]pyrimidin-2-amine TFA salt (50 mg, 0.077 mmol, yield 23.31%). LC-MS (M+H)+= 534_4. 4 NMR (500 MHz, MeOD) δ Ppm 7.43 (1 H, s), 7.40 (1 H, d, 7=8.55 Hz), 7.29-7.35 (3 H, m), 7.24 (1 H, dt, ^=8.62, 2.25 Hz), 7.16 (2 H, t, 7=8.09 Hz), 4.47 (1 H, br. s.), 4.23-4.35 (1 H, m), 4.12 (3 H, br. s.), 4.02 (1 H, br. s .)3 3.84-3.91 (3 H, m), 3.18-3.49 (2 H, m), 2.84 (3 H, s), 2.68- 2.81 (1 H, m), 2.56 (1 H, br. s. ), 2.35 (1 H, br. s.), 2.07-2.22 (1 H, m). Example 33 1 (4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl -7-(4-fluorophenyl)-4-(3-(methylamino)azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d] Diamine

^NH

Intermediate 33-1 1_(2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenylamino)-7-(4-fluorophenyl)-6,7 -Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(indenyl)amino decanoic acid tert-butyl ester 149653.doc -347- 201107311

F is a combination of 1-(2-chloro-7-(4-phenylene)-6,7-diar-phen-511-cyclopenta[d]pyrimidin-4-yl)azetidine according to the actual ^/25 -3-yl(decyl)amino decanoic acid tert-butyl ester (Nongken #//«) (147 mg, 0.340 mmol) and 4-(4-chloro-1H-flavored sal-i-yl)-3- Methoxyaniline (Nongban Qiang j) (76 mg '0.340 mmol) gives crude 1-(2-(4-(4-Ga-1H-imidazolyl)_3_nonyloxyphenylamino)_7_( 4_fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(indenyl)carbamic acid tert-butyl ester (1 〇4 mg, 0.168 mmol, yield 49.4%) was used without further purification. Lc_ms (M+H)+= 620.4 〇Example 33 According to: f do not 37 to make 1-(2-(4·(4-chloro-1Η-.mwowyl)-3-methoxyphenylamino) -7-(4-fluorophenyl)_6,7-dihydro·5H_cyclopenta[d]pyrimidin-4-yl)azetidin-3-yl(methyl)aminocarbamic acid tert-butyl The ester (R, 211 mg '0.340 mmol) was deprotected and purified to give N-(4-(4-H-1H-imidazol-1-yl)_3__ Oxyphenyl)_7_(4-fluorophenyl)_4-(3-(methylamino)azetidinium-yl)-6,7-dihydro-5H_cyclopenta[d] Pyrimidine-2-amine TFA salt (126 mg '0.199 mmol, yield 58.5%). LC-MS (M+H)+=520.4. NMR (500 MHz, MeOD) δ ppm 7·80 (1 149653.doc -348- 201107311 H,S),7.55(1H,d,J=2.14Hz),73i74〇(2H m),7 26_ 7.31(2H,m),7'09_7.2〇(3H,m),4 64 (2 H br s ) 4 46 (i H, t, J=7.93 Hz), 4.21-4.36 (1 H τ 〇7 , , m), 3.87 (3 H, s), 3.37 (2 H, s) ,3.11.3.21 (1 H,m),3.04 (1 H t ,,, ' UH, t5 /-14.95 Hz), 2.80- 2.84 (3 H,m), 2.68-2.80 (1 H 〇, — , m ), 2.14 (1 H, dddd, •/=13.28, 8·85, 6.56, 6.41 Hz). Example S 4

N-(4-(4-Chloro-IP methane-l-yl)imethoxyphenyl b$7-(dimethylamino)azetidinyl). 7♦ defeated base (4) Rhythm and enthalpy (4)

According to the actual employment of W2-chloro-7·(4-fluorophenyl)_6,7-dihydro-p-cyclopentane just bite 44) Ν, Ν_dimercaptoazetidine _3_amine (Nongxia lion (4) mg, 0.421 mmol) and 4-(4-gas-1Η-imidazole·u)_3_ methoxyaniline (Muller) (94 mg, 0.421 mmol) and purified to give a brownish Colloidal N-(4-(4-Gas-1H-Mimi&quot;Spin-1-yl)-3-methoxyphenyl)_4_(3_(didecylamino)azetidin-1- Base 7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d] ° dense. D-2-amine TFA salt (104 mg, 0.. 160 mmol, yield 3 8 · 1 ° / mp). LC-MS (M+H)+=534.4 〇!H NMR (500 MHz, MeOD) δ ppm 149653.doc •349· 201107311 7.82 (1 H, d, 7=1.53 Hz), 7 48 (1 H, d , 7=2.14 Hz), 7.39 (1 H' d, J~8·55 Hz), 7.35 (1 H,d,*/=1.53 Hz), 7.29-7.33 (2 H, m), 7.21 (1 H ,dd,J==8.55, 2.14 Hz), 7.11-7.18 (2 H, m), 4·83 (4 H, br. s.), 4.43-4 51 (l H, m), 4.30-4.37 ( 1 H, m), 3'88 (3 H,S), 312-3·22 (1 h, m), 3.04 (1 H, d, 7=6.10 Hz), 2.99 (6 H, s), 2.72 -2.84 u H,m,片〗.47, 8 98, 8 98, 4 58

Hz), 2.14 (i h, dddd, 16, 8 96, 6 56, 6 41 Hz). Example h N -(3-Fluoro-4_(3_r-yl)h,24_trisyl]-yl)phenyl b-7(4-fluorophenyl)-indole 4-methyl-6J-dihydro- 5Ηcyclopentyl And [d]pyrimidine_2 4_diamine

According to the combination of the actual Hungarian 26 2-gas j_(4_fluorophenyl)_Ν_曱yl_6,7-dihydro_5Η_cyclopenta[d]pyrimidine_4_amine (涝涝#///〇(164 Mg, 0.591 mmol) and 3_ fluoro-4-(3-methyl_1H-1,2,4-triazole·ι_yl)aniline (袅涝#5) (113 mg, 〇_591 mmol) and purified Obtained n2_(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-N4 as a white solid -methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine TFA salt (104 mg, 0.190 mmol, yield 32.2%). LC-MS (M+H) +=434.3. NMR (500 MHz, MeOD) δ ppm 8.75 (1 Η, d, /=2.44 Hz), 7.94 (1 Η, dd5 7=13.28, 2.29 Hz), 7.79 (1 H, t, J=8.70 Hz), 7.48 (1 H, 149653.doc -350- 201107311 dt, J~8.85, i Tt y'11 Hz), 7.27-7.35 (2 H, m), 7.10-7.19 (2 H, m), 4.51 (1 η η , va, ^=2.44 Hz), 3.18 (3 H, s), 2.89-2.98 (1 H, m), 2.74-2.87 o tr 〇' VH,m), 2.46 (3 H, s) , 2.09-2.23 (1 H, m). Example 36 N (4-(4-Amidazolyl).methoxyphenyl)7(4-fluorophenyl)-4-((S)-3-fluoropyrrolidine-fluorenyl)fluorene-dihydrogen -5H cyclopenta[morphopyrimidine-2-amine

Diastereomer A

2-Chloro-7-(4-fluorophenyl)_4_((s)-3-fluoro-hlrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (preparation Hpi) (3〇.5 mg, 0.091 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (26 4 mg, 0.118 mmol) Add AcOH (272 μ! 〇) to the solution in THF (272 pL). Heat the solution overnight at 10 ° C. Remove the solvent and dissolve the residue in MeOH. Prepare HPLC (50×250 mm HPLC Sunfire C18 10 μιη, 0 to 100% over 40 minutes A: Β, 100% Β 10 minutes (Α 90:10:0.1 water: MeOH: TFA; Β 90:10:0.1 MeOH: water: TFA)) Purification. Centrifuge concentrate (Speedvac) to the appropriate fraction to give N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)- 4-((S)-3-fluoro.pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine. LC-MS (M+H)+ =523.2. NMR (500 149653.doc -351 · 201107311 MHZ, CDCl3) δ PPm 7.74 (1 H,d,*7=2.14 Hz), 7.49 (1 H,d, 7-1.53 Hz), 7.12-7 19 (2 H, m), 7.05 (1 H, d, J=8.24 Hz), 6.95_7_01 (4 H,m), 6.84 (1 H,dd,7=8.55, 2.44 Hz), 5.35 (1 H ,td,J=52.87, 3.17 Hz), 4.07-4.17 (2 H,m), 4.04 (1 H,t, /-9.61 Hz), 3.80.3 94 (2 H, m), 3.58 (3 H, s), 3.25 (1 H, J-14.19' 9.00, 4.58 Hz), 3.05-3.14 (1 H, m), 2.55 (1 H,

Dddd, J-13.24, 3.74, 8.55, 4.58 Hz), 2.32-2.43 (1 H, m), 2.03-2.19 (1 H, m), 193_2 〇2 (1 H, m). Example 37 N-(4-(4-Chloro-1H, imidazolidinyl) 3 methoxyphenyl b 7 (4 fluorophenyl)· 4-((3)-3-. Bilobidine, 1 _基)_67_Dihydro_5}^-cyclopenta[0]pyrimidine-2-amine

Diastereomer B The preparation Hp2 and 4-(4-chloro-1H-imidazol-1-yloxylamine (Preparation A) were combined using the method of Example 36 to give N-(4-(4). - gas-1H-imidazol-1-yl)-3-decyloxyphenylfluorophenyl)-4-((S)-3-fluoroindol-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-2-amine. LC-MS (M+H)+=523.2.H NMR (500 MHz, CDC13) δ ppm 7.76 (1 Η, d, 7 = 1.83 Hz), 7.48 (1 H, s), 7.16 (2 H, dd, J=8.24, 5.49 Hz), 6.97-7.06 (4 H, m), 6.92 (1 H, s), 6.80 (1 H, dd, 7= 8.39, 1.98 Hz), 5.27- 149653.doc •352 · 201107311 5 42 〇Η, m)} 4.00-4.17 (3 Η, m), 3.80-3.94 (2 Η, m), 3.53 (3 Η, s) , 3.19-3.26 (1 Η, m), 3.08-3.17 (1 Η, m), 2.52-2.61 (1 Η, m), 2.32-2.43 (1 Η, m), 2.02-2.18 (1 Η, m) , 1.94 (1 Η, dq, *7=12.97, 8.60 Ηζ). Example 3 8

Ν-(4~(4-Ga-1Η-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)_ 4_((R)-夂-fluoropyrrolidine-丨-yl)-^7-dihydro-5H_cyclopenta[d]pyrimidine-2-amine

The preparations were combined with 4_(4_gas·1H-imidazolyl)-3-methoxyaniline (Preparation A) using the method of Example 36 to give a mixture of diastereomers. -(4♦chloro-1Hm_yl)_3methoxyphenyl)7 (4-milylphenylfluorofluorene.) pentylene (4) mixture of diastereomers

Waste. i/C-MS (M+H)+==523 2.丨 "· H NMR (500 MHz, MeOD) δ ppm 7.87 (1 H, s) 5 7.46-7.57 (1 H, m), 7.36.7.43 (2 H? m)&gt; 7.30-7.36 (2 H, m ), 7·24-7.3〇 (1 H, ton 7 u 7 i8 (2 &amp; (4), 5.34-5.57 (1 H, m), 4.33-4.52 (2 H, m), 4.07-4.26 (2 H, m), 3.93-4.01 (1 H, m), 3.9〇(3 H, s), 3.39-3.50 (1 H, m), 3.23- 3.31 (1 H, m)5 2.67-2.80 (1 H, m )} 2.21-2.54 (2 H, m), 2.07-2·18 (1 H, m). 149653.doc -353 - 201107311

Examples 38A and 38B N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-pyrrole Bitten-1-yl)-6,7-dihydro-5H-cycloindolo[d]pyrimidin-2-amine

Individual diastereomers were prepared by combining the preparation Hq with 4-(4-H-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) using the method of Example 36. a mixture of enantiomers. After preparative palm chromatography (25% MeOH, 0.1% DEA; OD-H chiral 30 x 250 nm column), the two diastereomers were separated. 38A: LC-MS (Μ+Η)+=523·2. 4 NMR (500 MHz, MeO£&gt;) δ ppm 7.84 (1 H, d, /=2.14 Hz), 7.68 (1 H, d, J =1.53 Hz), 7.19-7.24 (3 H, m), 7.16 (1 H, d, J=8.55 Hz), 6.99-7.09 (3 H, m), 5.29-5.45 (1 H, m), 4.05- 4.17 (3 H, m), 3.80-3.99 (2 H, m), 3.64 (3 H, s), 3.13 (1 H, dt, /=14.65, 7.32 Hz), 2.51-2.61 (1 H, m, 7=13.12, 8.70, 8.70, 4.58 Hz), 2.28-2.38 (1 H, m), 2.09-2.27 (1 H, m), 1.98 (1 H, dddd, 7=13.20, 8.62, 6.87, 6.71 Hz) 〇38B: LC-MS (M+H)+=523.2. NMR (500 MHz, δ ppm 7.86 (1 H, d, 7=2.14 Hz), 7.67 (1 H, s), 7.18-7.24 (3 H, I49653.doc -354- 201107311 m), 7.15 (1 H, d, J=8.55 Hz), 7.00-7.07 (3 H, m), 5.29-5.45 (1 H, m), 4.03-4.18 (3 H, m), 3.80-4.00 (2 H, m), 3.60 ( 3 H, s), 3.23-3.31 (1 H, m), 3.13-3.21 (1 H, m), 2.52-2.61 (1 H, m), 2.28-2.39 (1 H, m), 2.07-2.26 ( 1 H, m), 1.88-1.99 (1 H, m). Example 39 N-(4-(4-chloro-1H-imidazole-i•yl)methoxyphenyl)4_(44_difluoro brid% Small base) small (4-fluorophenyl)-6,7·dihydro-5Η·cyclopenta(4)pyrimidin-2-amine

The preparation was combined with 4-(4-chloro-1-indole-imidazolyl)-3-methoxyaniline (preparation a) using the method of Example 36 to give n-(4-(4-chloro-1H-imidazole). -1-yl)-3-methoxyphenyl)_4-(4,4-difluoropiperidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H- Cyclopenta(4)pyrimidin-2-amine (Example 39). LC-MS (Μ+Η)+=555·0. NMR (500 MHz, MeOD) δ ppm 7.68 (1 Η, d, J = 1.83 Hz), 7.55-7.59 (2 H, m), 7.18 (2 H, dd, 7=8.55, 5.49 Hz), 7.07-7.13 (2 H, m), 6.95-7.03 (3 H, m), 4.16 (1 H, t, J=8.39 Hz), 3.90 (4 H, t, J=5.34 Hz), 3.57 (3 H, s) , 2.97- 3.13 (2 H, m), 2.56-2.66 (1 H, m, 7=12.78, 8.49, 8.49, 3.81 Hz), 1.95-2.14 (5 H, m) 〇149653.doc -355 - 201107311 The racemic mixture was separated by palm chromatography to give the enantiomers of Examples 39A and 39B, which have the same spectral data. Example 40 N-(4-(4-Chloro-1H-imidazol-1-yl)_3_methoxyphenyl)_4_(4fluorodihydroacridine-1(2H)-yl)-7-(4- Fluorophenyl)_6,7-dihydro-5H-cyclopenta[magic acid H amine

The preparation was combined with the method of Example 36 to give N-(4-(4-H-1H-Mimi) with 4·(4_气_1H•oxazolyl)-3-decyloxybenamine (Preparation A) ' Salivation -3 -methoxyphenyl)-4-(4-fluoro-5,6-dihydro. 〇定定 1 (2H)-yl)-7-(4-fluorophenyl) -6,7-Dihydro-5H-cyclopenta[d] mouth bite-2-amine (Example 40). 1^(:- MS (Μ+Η)+=535·0. 4 NMR (500 MHz, CDC13) δ ppm 7.72 (1 H, d, /=1.83 Hz), 7.49 (1 H, d, /=1.53 Hz), 7.13-7.19 (2 H, m), 7.05 (1 H, d, 7=8.55 Hz), 6.97-7.02 (3 H, m), 6.95 (1 H, s), 6.77 (1 H, dd , J=8.55, 2.14 Hz), 5.31 (1 H,dt, /=14.80, 2.80 Hz), 4.18-4.33 (2 H, m), 4.15 (1 H, t, /=8.55 Hz), 3.99-4.06 (1 H, m), 3.80-3.88 (1 H, m), 3.51 (3 H, s), 2.98-3.12 (2 H, m), 2.58 (1 H, dddd, /=12.63, 8.55, 8.43, 3.66 Hz), 2.37-2.53 (2 H, m), 1.99 (1 H, dq, J=12.86, 8.33 149653.doc •356· 201107311

Hz). Separation of the racemic mixture by palm chromatography gave enantiomers Examples 40A and 40B, both having the same spectral data. Example 41 Ν-0Η4-gas-1H-isozolyl)·3_methoxyphenyl)_7_(4-fluorophenyl)_ 4-(3-(difluoromethyl). )_6 7_Dihydro-5ηcyclopenta (4) bite - 2-m

F. The preparation Ht was combined with 4-(4-a-1H-imidazole-i-yl)_3-nonyloxyaniline (Preparation A) using the method of Example 36 to give; Phenyl)-7-(4-fluorophenyl)_4_(3_(trifluoromethyl)σ-pyrrolidine q-yl)-6,7-two-year-cyclic and fdJ-pyrimidine-2-ammonium (Example 41) . Separation of a mixture of racemic diastereomers by palm chromatography followed by reverse phase chromatography gave individual enantiomers examples 4A, 41B, 41C and 41D. 41A: LC-MS (Μ+Η)+=573·1. H NMR (500 MHz, CDC13) δ ppm 7_84 (1 h, d, /=1.53 Hz), 7.49 (1 H, s), 7.15 (2 H, dd, 7=8.39, 5.34 Hz), 7.04 (1) H, d, 7=8.24 Hz), 6.95-7.02 (4 H, m), 6.72 (1 h, dd, /=8.39, 1.98 Hz), 4.11 (1 H, t, J=8.39 149653.doc 357- 201107311

Hz), 3.94-4.08 (2 H, m), 3.78-3.91 (2 H, m), 3.56 (3 H, s), 3.18- 3.27 (1 H, m), 2.97-3.14 (2 H, m) , 2.50-2.62 (1 H, m, J = 12.86, 8.60, 8.60, 4.12 Hz), 2.17-2.34 (2 H, m), 1.91-2.02 (1 H, m). 41B: LC-MS (M+H)+=573.1 » !H NMR (500 MHz, CDC13) δ ppm 7.84 (1 H,br. s·), 7.48 (1 H,d,*7=1.53 Hz), 7.11-7.22 (2 H, m), 6.95-7.09 (5 H, m), 6.69-6.78 (1 H, m), 4.12 (1 H, t, J=8.55 Hz), 3.95-4.08 (2 H, m), 3.77-3.92 (2 H, m), 3.55 (3 H, s), 3.21 (1 H, ddd, /=14.11, 8.93, 3.51 Hz), 2.98-3.16 (2 H, m), 2.51- 2.65 (1 H, m), 2.16-2.35 (2 H, m), 1.90-2.04 (1 H, m). 41C: LC-MS (M+H)+=573.1 〇NMR (500 MHz, CDC13) δ ppm 7.84 (1 H, br. s.), 7.48 (1 H, d, 7=1.53 Hz), 7.11-7.22 (2 H, m), 6.95-7.09 (5 H, m), 6.69-6.78 (1 H, m), 4.12 (1 H, t, J=8.55 Hz), 3.95-4.08 (2 H, m), 3.77-3.92 (2 H, m), 3.55 (3 H, s), 3.21 (1 H, ddd, 7=14.11, 8.93, 3.51 Hz), 2.98-3.16 (2 H, m), 2.51-2.65 (1 H, m), 2.16-2.35 (2 H, m), 1.90-2.04 (1 H, m). 41D: LC-MS (M+H)+= 573.1. 4 NMR (500 MHz, CDC13) δ ppm 7.84 (1 H, d, J=\.53 Hz), 7.49 (1 H, s), 7.15 (2 H, dd, 7=8.39, 5.34 Hz), 7.04 (1 H, d, 7=8.24 Hz), 6.95-7.02 (4 H, m), 6.72 (1 H, dd, 7=8.39, 1.98 Hz), 4.11 (1 H, t5 /=8.39 Hz), 3.94-4.08 (2 H, m), 3.78-3.91 (2 H, m), 3.56 (3 H, s), 3.18- 3.27 (1 H, m), 2.97-3.14 (2 H, m), 2.50-2.62 (1 H, m, 149653.doc •358 · 201107311 J 12.86, 8.60, 8.60, 4.12 Hz), 2.17-2.34 (2 H, m), 1.91-2.02 (1 H, m). Example 42 N2-(4-(4-Chloroimidazolyl)3methoxyphenyl)N4_(3-ethoxypropyl)-7-(4-fluorophenyl)6,7·dihydro·5Η ring Pentylene [morphine-24 diamine

The preparation Hu was combined with 4-(4- gas-1 Η-imidazol-1-yl 3-methoxyaniline (Preparation A) using the method of Example 36 to give N2-(4-(4- gas-1H-). Imidazolyl-1-yl)-3-decyloxyphenyl)-N4_(3-ethoxypropyl)7-(4-fluorophenyl)_6,7-nitrogen·5Η_azapenta[d]pyrimidine-2 , 4-diamine (Example 42). LC-MS (M4-H)+=537.2 NMR (500 MHz, CDC13) δ ppm 7.91 (1

H,d, "7-2.14 Hz", 7.48 (1 H,d,*7=1.53 Hz), 7.12-7.19 (2 H, m), 7.03 (1 H,d,&lt;/=8.55 Hz), 6.94-7.01 (4 h,m), 6.74 (1 H, dd, 7=8.55, 2.14 Hz), 5.45 (1 H, t, J=4.73 Hz), 4.14-4.21 (1 H, m), 3.61- 3.71 (4 H, m), 3.46-3.57 (5 H, m), 2.63 (2 H, dd, &gt; 8.85 ' 6.41 Hz), 1.96-2.05 (1 H, m), K93 (2 h, five weights Peak, · 7 = 5 · 72 Hz), 1.25 (3 H, t, · 7 = 7.02 Hz). Example 43 3 (2_(4·(4_chloro_111_咪嗤_1_yl)_3_methoxyphenylamino) small (4-phenylphenyl)_6,7-dihydro-5Η-cyclo Pentative [d]pyrimidine _4_ylamino)propanol 149653.doc • 359-201107311

F. The preparations 1 and 4_(4_gas_1^1 imidazolyl)-3-methoxyaniline (preparation A) were combined using the method of Example 36 to give 3-(2-(4-(4) -Chloro-indole-imidazol-1-yl)-3-methoxyphenylamino)-7(4-fluorophenyl)-6,7-dihydro-5H_cyclopenta[d]. 4-Aminoamino)propan-1-ol (Example 43). LC-MS (M+H)+= 509.3. 4 NMR (500 MHz,MeOD) δ ppm 7.87 (1 η,d, ^=2.14 Hz), 7.68 (1 H, d, J=1.53 Hz), 7.19- 7.26 (3 H, m), 7.16 (1 H, d, J=8.55 Hz), 7.01-7.09 (3 H, m), 4.19 (1 H, t, 7=8.09 Hz), 3.64-3.72 (4 H , m), 3.61 (3 H, s), 2.77-2.86 (1 H, m), 2.60-2.74 (2 H, m), 1.96-2.06 (1 H, m), 1.90 (2 H, qd, J =6.46, 6.26 Hz) ° The racemic mixture was separated by palm chromatography to give enantiomers, Examples 43A and 43B, which have the same spectral data. Example 4 4 7-(4-Fluorophenyl)-yl-(3-methoxy-4-(3-methyl_1-1,2&gt;4-tris.-l-yl)phenyl)- N4-methylindoledihydro-5H-cyclopenta[d]pyrimidine_2,4 diamine

2-Chloro-7-(4-fluorophenyl)-N-fluorenyl-6,7-dialdehyde_5H_cyclopenta[d]pyrimidine-360-149653.doc 201107311 bite-4-amine (preparation Hh) (141.2 mg, 0.508 mmol) and 3-decyloxy-4-(3-methyl-1H-1,2,4-triazole-i-yl)aniline (Preparation D) (2〇8, 1.017 mmol) H2S04 (43.4 pL, 0.813 mmol) was added to a solution of N-decyl-2-pyrrolidone (4067 μί). Heat the solution to 1 Torr. Hey. When the reaction is complete, water and NaHC〇3 are added. After extraction, the organic extract was dried over MgSO4, filtered and concentrated in vacuo. The residue was applied to SG and eluted with EtOAc/Hex gradient to afford 7-(4-fluorophenyl)-N.sub.2-(3-methyl-l-l-l-l-l, 1_yl)phenyl)_N4_methyl_6,7-dihydro-5H-cyclopenta[d] mouth. _2,4_Diamine (Example 44). LC-MS (Μ+Η)+=446·1. NMR (500 MHz, CDC13) δ ppm 9.43 (1 Η, br. s.), 8.47 (1 H, s), 7.77 (1 H, br. s.), 7.54 (1 H, d, J=8.85 Hz ), 7.14-7.20 (2 H, m), 6.99 (2 H, t, /=8.55 Hz), 4.88 (1 H, br. s.), 4.24-4.31 (1 H, m), 3.71 (3 H , s), 3.15 (3 H,d,*7=4.90 Hz), 2.73-2.82 (1 H,m), 2.63-2.72 (2 H, m), 2.46 (3 H, s), 2.06-2.16 ( 1 H? m) ° The above racemic materials were separated by SFC for palm chromatography to give individual enantiomers (Examples 44A and 44B). SFC **: Chiralpak〇JH (30xl50 mm), 30% methanol in C02 (〇1% diethylamine), 1 bar (bar) 'flow rate 50 mL/min' maintained for 12 minutes, 268 nm absorbance, injection 2.0 A solution of mL 10 mg/mL in methanol, tR (peak A) = 4 7 min, tR (peak Β) = 9.6 min. The absolute stereochemistry of the individual enantiomers (Examples 44A and 44B) was not determined. 44A: LC-MS (M+H)+ = 446.2. IX Rt 13.03 minutes (Waters Sunfire 4.6x150 mm '1〇〇/0 to 100〇/〇b in 15 minutes a, 1.5 149653.doc -361 - 201107311 mL/min (A is 90:l〇:〇.i Water: MeOH: TFA; B: 90:10:0.1 MeOH: water: TFA)). NMR (500 MHz, DMSO-d6) δ ppm 9_22 (1 H, s), 8.58 (1 H, s), 8.18 (1 H, s), 7.30 (1 H, d, J = 8.85 Hz), 7.22 ( 2 H, t, J=6.26 Hz), 7.08-7.16 (3 H, m), 6.93-6.99 (1 H, m), 4.17 (1 H, t, J=8.09 Hz), 3.63 (3 H, s ), 2.97 (3 H, d, J=4.27 Hz), 2.72-2.81 (1 H, m), 2.53-2.66 (2 H, m), 2.31 (3 H, s), 1.85-1.95 (1 H, m) = 13C NMR (126 MHz, DMSO-d6) δ ppm 170.7, 160.7 (d, J = 241.3 Hz), 159.7, 159.6, 159.2, 151.4, 145.0, 142.9, 140.4 (d, J = 2.7 Hz), 129.8 (d, J = 7.8 Hz, 2C), 124.6, 117.9, 114.9 (d, J = 20.9 Hz, 2C), 109.6, 108.1, 101.5, 55.2, 50.4, 32.7, 27.4, 25.4, 13.5 ° [a]D- 69.13° (c 2.67, CHC13). Example 45 N2-(4-(4-Azamidazolyl-methyl, methoxyphenylcyclopropyl-2-methoxyethyl)-7-(4-fluorophenyl)-6,7-di Hydrogen-5H-cyclopenta[d]. guanidine-2,4-diamine

The preparation Hw was combined with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) using the method of Example 7 to give N2-(4-(4-chloro-1H). -imidazol-1-yl)-3-methoxyphenyl)·Ν4-(1·cyclopropyl-2-methoxyethyl)-7-(4-fluorobenzene 149653.doc •362 - 201107311 -6,7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 45). A mixture of the racemic diastereomers was separated by chromatography, followed by reverse phase chromatography to afford the individual enantiomers 45A, 45B, 45C and 45D. 45A: LC-MS (Μ+Η)+=549·3. 4 NMR (500 MHz, CDC13) δ ppm 10.75 (1 H, br. s.), 7.40 (1 H, d, J = 8.24 Hz), 7.22- 7.29 (3 H, m), 7.15-7.21 (3 H, m), 6.99-7.08 (2 H, m), 5.97 (1 H, d, /=8.24 Hz), 4.42-4.50 (1 H, (m), 3.84 (3 H, s), 3.78 m), 2.82 (2 H, t, 7=8.55 Hz), 2.21-2.32 (1 H, m), 1.15-1.27 (1 H, m), 0.62-0.70 (1 H, m), 0.53-0.62 ( 1 H, m), 0.39 (1 H, ddd, /= 9.46, 5.19, 4.88 Hz), 0.26-0.33 (1 H, m). 45B: LC-MS (M+H)+ = 549.3. NMR (500 MHz, CDC13) δ ppm 10.58 (1 H, br. s.), 7.40 (1 H, d, J = 8.85 Hz), 7.22- 7.29 (3 H, m), 7.14-7.20 (3 H, m), 7.04 (2 H, t, J=8.39 Hz), 6.02 (1 H, d, /=8.24 Hz), 4.45 (1 H, d, J=3.66 Hz), 3.84 (3 H, s), 3.71-3.79 (1 H, m), 3.63 (2 H, d, J=3.05 Hz), 3.42 (3 H, s), 2.91 (1 H, d, /=9.46 Hz), 2.79 (2 H, dd , J-8.70, 5.34 Hz), 2.21-2.31 (1 H, m), 1.19 (1 H, dt, «7=8.55, 4.27 Hz), 0.62-0.70 (1 H, m), 0.54-0.62 (1 H, m), 0.39 (1 H, dq, /=9.54, 4.86 Hz), 0.24-0.33 (1 H, m). 45C: LC-MS (M+H)+ = 549.3. NMR (500 MHz, CDC13) δ ppm 10.75 (1 H, br. s.), 7.40 (1 H, d, 7=8.24 Hz), 7.22- 149653.doc • 363 - 201107311 7.29 (3 H, m), 7.15-7.21 (3 Η, m), 6.99-7.08 (2 Η, m), 5.97 (1 Η, d, 7=8.24 Hz), 4.42-4.50 (1 H, m), 3.84 (3 H, s) , 3.78 (1 H, t, J=8.09 Hz), 3.63 (2 H, br. s.), 3.43 (3 H, s), 2.86-2.97 (1 H, m), 2.82 (2 H, t, J=8.55 Hz), 2.21-2.32 (1 H, m), 1.15-1.27 (1 H, m), 0.62-0.70 (1 H, m), 0.53-0.62 (1 H, m), 0.39 (1 H , ddd, J=9.46, 5.19, 4.88 Hz), 0.26-0.33 (1 H, m). 45D: LC-MS (M+H)+ = 549.3. NMR (500 MHz, CDC13) Sppml 0.58 (1H, br. s.), 7.40 (lH, d, J = 8_85 Hz), 7.22- 7.29 (3H, m), 7.14-7.20 (3 H, m), 7.04 (2 H, t, J=8.39 Hz), 6.02 (1 H, d, 7=8.24 Hz), 4.45 (1 H, d, J=3.66 Hz), 3.84 (3 H, s), 3.71-3.79 (1 H, m), 3.63 (2 H, d, /=3.05 Hz), 3.42 (3 H, s), 2.91 (1 H, d, J=9A6 Hz), 2.79 (2 H, dd, J= 8.70, 5.34 Hz), 2.21-2.31 (1 H, m), 1.19 (1 H, dt, /=8.55, 4.27 Hz), 0.62-0.70 (1 H, m), 0.54-0.62 (1 H, m) , 0.39 (1 H, dq, /=9.54, 4.86 Hz), 0.24-0.33 (1 H, m) ° Example 46 N2-(4-Chloro-1H-imidazol-1-yl)-3-methyl Oxyphenyl)-7-(4-fluorophenyl)-]^4,:^-dimethyl-6,7-dihydro-51{-cyclopenta[ phenanthroline-2,4-diamine

2-Ga-7-(4-fluorophenyldimercapto-6,7-dihydro-5if-cyclopenta[d] 149653.doc •364· 201107311 Pyrimidine-4.amine (268 mg, 0.919 mmol Add to a solution of 4-(4-carbo-l/f-imidazo-i-yl)-3-nonyloxyaniline (205 mg, 0.919 mmol) in THF (1 mL)EtOAc. The reaction mixture was stirred overnight at 75 ° C. The crude reaction mixture was purified by preparative HPLC eluting the appropriate fractions to give W-(4-(4- s. Oxyphenyl)-7-(4-fluorophenyl)-#, fluorenyl-dimercapto-6,7-dihydro-5/f-cyclopenta[d]pyrimidine-2,4-diamine TFA Salt (60.7 mg '0.095 mmol, yield 10.36%). LC-MS (M+H)+===================================================== J=1.5 Hz), 7.39 (2H, d, J=2.\ Hz), 7.22 (1H, d, J=5.2 Hz), 7.15 (1H, d, J=8.5 Hz), 6.96-7.07 (3H, m), 5.29 (1H, s), 4.29-4.38 (1H, m), 3.81 (3H, s), 3.50-3.57 (1H, m), 3.43-3.49 (1H, m), 3.31-3.39 (3H, m), 3.16-3.26 (2H, m), 3.09-3.14 (1H, m), 2.58-2.72 (1H, m), 2.5 2 - 2 · 5 8 (1H, m ), 2 · 13 - 2.2 5 ( 1H, m).

Examples 46A and 46B (S)-N2-(4-(4-chloro-1H-imidazolyl-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-1^4, ^-Dimethyl-6,7-dihydro-51{-cycloindolo[0]° sessile-2,4-diamine oxime (R)-N2-(4-(4-gas-1Η-imidazole) -1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine

149653.doc 365· 201107311 Purification using palmitic SFC ^-(4-(4-Gas-l/f-imidazolyl)_3_methoxyphenyl)-7-(4·fluorophenyl)_#之外·Dimethyl_6,7-dihydro_5 ft-cyclopenta[d]pyrimidine-2,4-diamine racemic mixture (not #), to obtain peak A (true and peak Β (:Τ不#5). SFC method __ chiralpak OJ-H (4.6x250 mm, 5 μΜ), (: 02% sterol (0.1 〇 / 〇 diethylamine), 35 ° C, flow rate 2.0 mL /min, maintained for 14 minutes, 268 nm absorbance, injection of 5 2 mg / mL solution in methanol (multiple stack injection), iR (peak α) = 4 3 minutes, Q (peak B) = l 〇. 8 minutes The absolute stereochemistry of the individual enantiomers (Purple Hungarian and 4Μ) was not determined. The lc_ms and ιΗ NMR data of the separated enantiomers were identical to those of the racemate (see μ). Example 47 Ν2- (4·(4_Gas-1Η-imidazole small group) Winter methoxyphenyl) small (4-fluorophenyl)_ Ν-di-methylmethyl-6,7-dichloro-5Η-cycloindole[ d] mouth bite-2,4-diamine

2-Chloro-7-(4-fluorophenyltrimethyl-6,7-dihydro-5 ugly-cyclopenta[(1]°3⁄4 η 4-amine (47.5 mg, 0.169 mmol) And a solution of 4-(4-chloro-1//-imidol-1-yl)-3-methoxyaniline (37.8 mg '0.169 mmol) in THF (1 mL) and acetic acid (1 mL) The mixture was heated overnight at ° C. The product was purified by reverse phase preparative HPLC to give a brown oil. y^((4_(4_chloro_丨open_imidazol-1-yl)-3-decyloxy Base)-7-(4-fluorophenyl•tris-methyl_6,7_two 149653.doc -366- 201107311 Hydrogen-5//-cyclopenta[d]pyrimidine-2,4-diamine TFA Salt (33.3 mg, 0.057 mmol 'yield 33.8%). LC-MS (M+H)+= 467.9. NMR (500 MHz, CDC13) δ ppm 11.21 (1H, s), 8.35-9.96 (1H, m) , 8.20 (1H, s), 7.51 (1H, s), 7.43 (1H, d, /=8.5 Hz), 7.25 (1H, s), 7.22 (1H, d, J=8.9 Hz), 7.14-7.20 ( 2H, m), 7.01 (1H, t, J=8.5 Hz), 5.98 (1H, s), 4.43 (1H, d, J=4.6 Hz), 3.85 (3H, s), 2.88 (1H, d, / =9.5 Hz), 2.69-2.83 (2H, m), 2.20-2.32 φ (lHsm) 〇 Example 4 8 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxybenzene -7-(4-fluorophenyl)-N4-((R)-l-methoxybutan-2-yl)-6,7-dihydro-5H-cyclo And [d] anger. 2,4-diamine a given person ¥ salt

Ci-〇n diastereomeric mixture such that 2·gas-7-(4-fluorophenyl)-N-((R)-l-decyloxybut-2-yl)_6,7-dihydro- 511 -% pentame |^]. The intimate _4_amine (prepared from the preparation) and 4_(4_qi_1 仏 唾 -1--1-yl)-3 methoxyaniline (preparation A) were reacted as described in Example ,12, In the form of a mixture of two diastereomers ^^(4(4_chloro_111_米坐_1_yl)_3_methoxyphenyl)_7_(4~fluorophenyl)-N4- ((R)-l-methoxy 149653.doc •367·201107311 But-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine diTFA salt (Example 48). LC-MS (M+H)+ = 537.5. NMR (500 MHz, CDC13) δ ppm 11.66 (br· s·,1 Η) 7·99 (s,1 Η) 7.51 (d, J=8.85 Hz, 1 H) 7.32 (dd, J=8.85, 1.83 Hz , 1 H) 7.18-7.30 (m, 4 H) 7.04 (td5 J=8.62, 1.68 Hz, 2 H) 5.83 (t, J=9.61 Hz, 1 H) 4.43- 4.51 (m, 1 H) 4.28-4.39 (m, 1 H) 3.87 (s, 3 H) 3.51-3.64 (m, 2 H) 3.38-3.49 (m, 3 H) 2.87-3.00 (m, 1 H) 2.75-2.85 (m, 2 H) 2.24 -2.35 (m, 1 H) 1.69-1.87 (m, 2 H) 0.97-1.06 (m, 3 H) 分离 separated by a mixture of two diastereomers by palm chromatography Examples of two diastereomeric forms of the amine form 48 A and 48B. Example 48A: LC-MS (M+H)+ = 537.4. NMR (500 MHz,

MeOD) 5 ppm 7.86 (d, J=2.14 Hz, 1 H) 7.66 (d, J=1.53 Hz, 1 H) 7.16-7.25 (m, 3 H) 7.10-7.16 (m, 1 H) 6.99-7.07 ( m, 3 H) 4.45-4.53 (m, 1 H) 4.17 (t, J=8.24 Hz, 1 H) 3.61 (s, 3 H) 3.56 (dd, J=9.46, 5.80 Hz, 1 H) 3.44-3.51 (m, 1 H) 3.37 (d, J=7.02 Hz, 3 H) 2.76-2.86 (m, 1 H) 2.59-2.75 (m, 2 H) 1.94-2.04 (m, 1 H) 1.73-1.85 (m , 1 H) 1.54-1.66 (m, 1 H) 0.99 (t, J = 7.48 Hz, 3 H) = Example 48B: LC-MS (M+H)+ = 537.4. 4 NMR (500 MHz,

MeOD) δ ppm 7.86 (d, J=2.14 Hz, 1 H) 7.67 (d, J=1.53 Hz, 1 H) 7.18-7.26 (m, 3 H) 7.11-7.16 (m, 1 H) 6.97-7.08 ( m, 3 H) 4.44-4.53 (m,1 H) 4.17 (t, J=8.〇9 Hz, 1 H) 3.61 (s,3 H) 3.55 (dd, J-9.46, 5.49 Hz, 1 H) 3.46 (dd, J=9.61, 5.65 Hz, 1 -368-149653.doc 201107311 Η) 3.35-3.41 (m, 3 9 ηη ^ 2·77-2.87 (m, 1 Η) 2.67-2.76 (m, 1

Η) 2,64 (ddd, J=12.44 R 5 8·62, 3.66 Hz, 1 Η) 1.93-2.07 (m, 1 Η) 1.80 (ddd, J=13 50 ι πλ ., 7.71, 5.34 Hz, 1 Η) 1.56-1.68 (m, 1 H) 1.01 (t, J = 7.48 Hz, 3 h). Example 49 -yl)-3-indolyloxyphenyl)-N4-((R)-1-cyclo N2-(4-(4-chloroindolylethyl)-7-(4-fluorophenyl) )_6,7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-

Diamine diTFa salt

F mixture of diastereomers gives 2-chloro-N-((R)-1-cyclopropylethyl)7-(4-fluorophenyl)6,7-dihydro-5H-% penta[d Pyrimidine-4-amine (preparation Hy) and 4-(4-chloro-1H-imidazolyl)-3-nonyloxyaniline (preparation A) were reacted as described in Example ,2 to give two a mixture of diastereomers in the form of a mixture of salin-1-yl)-3-decyloxyphenyl)-m-((R)-l-cyclopropylethyl)-7-(4-fluorophenyl -6,7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine diTFA salt (Example 49). LC-MS (M+H)+=519.5. 4 NMR (500 MHz, CDC13) δ PPm 11.81 (s,1 Η) 7.85 (s,1 Η) 7.38-7.48 (m,2 Η) 7.28 (s, 1 H) 7.26 (ddd, J=8.77, 5.11, 1.98 Hz, 1 H) 7.12 (d5 J = 1.22 Hz, 1 H) 7.04 (td, J=8.62, 1.68 Hz, 2 H) 5.65 (t, J=7.02 Hz, 149653.doc -369- 201107311 4.52 (m,1 Η) 3.73-3.88 (m,4 Η) 2.88-3.01 (m,1 )2·88 (m, 2 H) 2.25-2.39 (m, i H ) 1.40 (dd, J=6.56, 4·12 3 H) 0.99-1.14 (m, j H) 0.65-0.75 (m, 1 H) 0.53- 0 64 (m,1 H) 〇·39 ^ J=9 -8〇5 5.00 Hz, 1 H) 0.27-0.35 (m,

1 H) ’ 'V' sub-drugs were chromatographed to separate a mixture of the two diastereomers to give the two diastereomeric examples 49A and 4 in the form of the amine. Example 49A: LC-MS (M+H) + = 519.3. Towel NMR (500 MHz,

MeOD) δ ppm 7.87 (d, J=2.14 Hz, 1 H) 7.66 (d, J=1.53 Hz, 1 H) 7.17-7.28 (m, 3 H) 7.08-7.17 (m, 1 H) 6.90-7.08 ( m, 3 H) 4.15 (t, J=8.24 Hz, 1 H) 3.78-3.92 (m, 1 H) 3.59 (s, 3 H) 2.75-2.85 (m, 1 H) 2.59-2.74 (m, 2 H ) 1.33 (d, J=6.71 Hz, 3 H) 1.00-1.14 (m, 1 H) 0.82-1.00 (m, 1 H) 0.39-0.59 (m, 3 H) 0.26 (dt, J=9.38, 4_62 Hz , 1 H). Example 49B: LC-MS (M+H) + = 519.3. NMR (500 MHz,

MeOD) δ ppm 7.87 (d, J=2.14 Hz, 1 H) 7.66 (d, J=1.53 Hz, 1 H) 7.15-7.25 (m, 3 H) 7.13 (d, J=8.55 Hz, 1 H) 7.02 (t, J=8.85 Hz, 2 H) 6.98 (dd, J=8.55, 2.14 Hz, 1 H) 4.16 (t, J=8.09 Hz, 1 H) 3.82-3.98 (m, 1 H) 3.60 (s, 3 H) 2.78-2.87 (m, 1 H) 2.55-2.75 (m, 2 H) 1.91-2.04 (m, 1 H) 1.35 (d, J=6.71 Hz, 3 H) 0.79-0.98 (m5 1 H) 0.55 (td, J=8.70, 4.27 Hz, 1 H) 0.45-0.51 (m, 1 H) 0.32-0.43 (m, J=9.65, 5.04, 4.86, 4.86 Hz, 1 H) 0.16-0.29 (m,1 H). Example 50 149653.doc -370 - 201107311 N2-(4-(4-Ga-1H-imidazole-buyl)·,methoxyphenylcyclopropylethyl)-7-(4-fluorophenyl)_6&gt ;7_Dihydro 5}1_cyclopenta[(1]pyrimidine_2,4_

A mixture of diastereomers gives 2-a-N-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d] Pyrimidine-4-amine (preparation 112) was reacted with 4_(4_gas_111_imidazo-bu)-3-decyloxyaniline (preparation A) as described in Example 112 to give two non- N2_(4_(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-((S)-i-cyclopropylethyl)_7_ as a mixture of enantiomers (4-Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]. Bite 2,4-diamine TFA salt (example φ 50) ° LC-MS (Μ+Η)+=519.5 ° 'Η NMR (500 MHz, CDC13) δ ppm 11.84 (s, 1 H) 7.80 (s , 1 H) 7.43 (s3 1 H) 7.41 (d, J-8.85 Hz, 1 H) 7.28 (s, 1 H) 7.26 (ddd, J=8.70, 5.19, 1.98 Hz, 1 H) 7.19 (d, 1 =8.55 Hz, 1 H) 7.11 (s, 1 H) 7.04 (td5 J=U2, 1.68 Hz, 2 H) 5.66 (t, J=6.87 Hz, ! H) 4 4〇4 52 (m, 1 H) 3.72-3.87 (m, 4 H) 2.87-3.07 (m, 1 H) 2.67-2.86 (m, 2 Η) 2.26-2.40 (m, 1 H) 1.40 (4), j=6.56, 4.12 Hz, 3 H) 1.03 -1.15 (m,1 Η) 0.56-0.76 (m,2 H) 0.29-0.49 (m, 2 H). By separating the mixture of the two diastereomers by palm chromatography, 149653.doc -371 - 201107311 to the two diastereomeric examples 5A and 50B in free amine form. Example 50A: LC-MS (M+H) + = 519.3. *H NMR (500 MHz, MeOD) δ ppm 7.88 (d, J=2_14 Hz, 1 Η) 7.67 (d, J = 1.53 Hz, 1 H) 7.17-7.24 (m, 3 H) 7.14 (d, J= 8.55 Hz, 1 H) 6.90-7.08 (m, 3 H) 4.18 (t5 J = 8.09 Hz, 1 H) 3.88 (dd, J = 8.09, 6.56 Hz, 1 H) 3.61 (s, 3 H) 2.77-2.89 (m, 1 H) 2.58-2.77 (m, 2 H) 1.90-2.05 (m, 1 H) 1.35 (d, J=6.71 Hz, 3 H) 1.07 (dt, J=8.24, 4.88 Hz, 1 H) 0.51-0.57 (m, 1 H) 0.44-0.51 (m, 1 H) 0.40 (dd, J = 9.61, 4.73 Hz, 1 H) 0.17-0.29 (m, 1 H). Example 50B: LC-MS (Μ+Η)+=519·3. 4 NMR (500 MHz, MeOD) δ ppm 7.87 (d, J = 1.83 Hz, 1 H) 7.67 (s, 1 H) 7.20-7.27 ( m, 3 H) 7.14 (d, J=8.55 Hz, 1 H) 6.93-7.08 (m, 3 H) 4.17 (t, J=8_24 Hz, 1 H) 3.75-3.93 (m,1 H) 3.61 (s ,3 H) 2.76-2.88 (m, 1 H) 2.54-2.73 (m, 2 H) 1.89-2.08 (m, 1 H) 1.34 (d, J=6.71 Hz, 3 H) 0.99-1.12 (m, 1 H) 0.54-0.63 (m, 1 H) 0.46-0.54 (m, 1 H) 0.43 (dd, J = 9.61, 4.73 Hz, 1 H) 0.18-0.28 (m, 1 H). Example 51 N2-(4-(4-Chloro-1H-.s-l-yl)-3-methoxyphenyl)·v4-methyl-8-phenyl-7,8-dihydro-51{ -&lt;1 bottom ° South and [4,3-(1]° dense bite-2,4-diamine

372· 149653.doc 201107311 According to the real 26 combination 2-chloroindolyl_8_phenyl_7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine ^α) (125 mg, 0.453 mmol) and 4·(4-gas-1H-flavor. sit-1-yl)-3_decyloxyaniline (裘潆 and ^) (1〇1 mg, 0.453 mmol) And purification, to obtain a yellowish yellow glass-cleared N2_(4-(4-gas·lH-miso-l-yl)-3-methoxyphenyl; l·N4-methyl-8-phenyl- 7,8-Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (178 mg, 0.309 mmol ' yield 68.1%). LC-MS (M+H) +=463.2.4

NMR (500 MHz, MeOD) δ ppm 7.81 (1 Η, s), Ί.62 (1 Η, s), 7.32-7.47 (7 Η, m), 7.14 (1 Η, dd, J=8.55, 2.14 Hz ), 4.54-4.72 (2 H, m), 4.19 (1 H, dd, 7=11.44, 4.73 Hz), 4.10 (1 H, t, 7=4.43 Hz), 3.94 (1 H, dd, 7=11.44 , 4.73 Hz), 3.86 (3 H, s), 3.15-3.19 (3 H, m) 〇

Example 51A N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-7,8-dihydro-5H-Brig Taste [4,3-d] ° bite-2,4-diamine

NH

Isolation of N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methyl by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ, EtOH/heptane) Oxyphenyl)-N4-methyl-8-phenyl-7,8-dihydro-5H-piperazo[4,3-d]pyrimidine-2,4-diamine afforded as a yellow solid N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-7,8-dihydro-5H-pyran 149653 .doc -373 · 201107311 And [4,3-d]pyrimidine-2,4-diamine TFA salt (·first eluted, enantiomer A) (36.5 mg, 0.063 mmol). LC-MS (M+H)+=463.2. 4 NMR (500 MHz, MeOD) δ ppm 7.83 (1 H, br. s.), 7.70 (1 H, br. s.), 7.35 (2 H, t , /=7.32 Hz), 7.24-7.33 (4 H, m), 7.21 (1 H, d, 7=8.55 Hz), 6.97-7.05 (1 H, m), 4.52-4.71 (2 H, m), 4.16 (1 H, dd, J=11.44, 4.73 Hz), 3.98 (1 H, br. s.), 3.87-3·96 (1 H,m), 3.61 (3 H,br· s.),3.06 -3.14 (3 H, m). The absolute stereochemistry of the real eve of 5M has not been determined.

Example 51B N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N,methyl-8-phenyl-7,8-dihydro-5H-piperidin Cyclo[4,3-d]pyrimidine-2,4-diamine

Separation of N2-(4-(4-Ga-1H-imidazole-indolyl)_3-methoxy by multiple preparative HPLC injections (OJ-H 30x250 mm, 10 μΜ ' EtOH/heptane) The basic group)-N methyl-8-phenyl-7,8-diin-5Η-α-deoxy[4,3-£1] is dense. 2,4-Diamine, N2-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxyphenyl)-N4-indolyl-8- as a yellow solid Phenyl-7,8-dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (second elution, enantiomer)

B) (30.9 mg '0.054 mmol). LC-MS (M+H)+ = 463. 'H NMR (500 MHz, MeOD) δ ppm 7.74 (2 H, br. s.), 7.24-7.48 (7 H, m), 7.01-7.13 (1 H, m), 4.52-4.73 (2 H, m ), 4.17 (1 H, 149653.doc -374- 201107311 dd, /=11.44, 4.73 Hz), 4.00-4.11 (1 H, m), 3.88-4.00 (1 H, m), 3·71 (3 H , br. s·), 3.12 (3 H, s). Absolute stereochemistry not measured. Example 52 n2-(4-(4-Chloridazol-1-yl)-3-methoxyphenyl)-N4-ethyl-N4-methyl-8-phenyl-7,8-dihydro-5H_ Piperido[4&gt;3-phasicin-24-diamine

To 2-oxoethyl-fluorenyl-fluorenyl-8-phenyl-7,8-dihydro-5//-piperano[4,3-pyrimidin-4-amine (146 mg, 0.481 mmol) and 4-(4-Ga-1//-imidazole-1·yl)·3·decyloxyaniline (107 mg, 0.481 mmol) in THF (1.0 mL) The reaction mixture was stirred at 75 ° C overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions affords the ore-(4-(4-carb-1-imidazol-1-yl)-3-methoxyphenylethylmercapto-8-phenyl-7,8-dihydro- 5//-piperido[4,3-pyrimidine-2,4-diamine TFA salt (59.9 mg, 0.092 mmol, yield 93%). LC-MS ( Μ+Η)+=491.4. 500 MHz, CDC13) δ ppm 11.77 (1H, s), 7.67 (1H, d, J=1.5 Hz), 7.39 (1H, dd, /=8.5, 2.1 Hz), 7.26-7.35 (5H, m), 7.16 (1H, s), 7.14 (1H, s), 7.06 (1H, d, 7 = 1.5 Hz), 4.75-4.90 (2H, m), 4.14-4.23 (2H, m), 3.90 (1H, d, 7 =7.0 Hz), 3.81 (3H, s), 3.62 (2H, s), 3.27 (3H, s), 1.34 (3H, t, J = 7.2 Hz). 149653.doc •375 · 201107311

Examples 52A and 52B (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-N4-methyl-8-phenyl -7,8-Dihydro-5Η-σ-deoxy[4,3-d]. Cough-2,4-diamine(R)-N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_N4·ethyl_N4-methyl- 8-phenyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine

Purification of iV2-(4-(4-Ga-1)-imidazol-1-yl)-3-yloxyphenyl)-8-(4-fluorophenyl)-indole, diterpene group using palmitic SFC -5,6,7,8-Tetrahydroquinazoline-2,4-diamine racemic mixture (55.0 mg, 0.112 mmol) (actually "52", paid to peak · Α (17_2 mg, 0.035 Methyl) (real 52^4) and &gt;*%B (18.8 mg, 0.038 mmol) (real 525). SFC method: Chiralpak OJ-H (3〇x250 mm, 5 μΜ) ‘C02 35% methanol (〇_1〇/0 diethylamine), 35. 〇, flow rate 7〇mL/min, maintain 13 minutes '268 nm absorbance' injection 5 pL 27 mg / mL solution in sterol (multiple stack injection), ~ (♦ a) = 4.2 minutes, (peak B) = 8.3 minutes. The LC-MS and 1H NMR analytical data for the enantiomers of the absolute stereochemical oxime separation of the individual enantiomers (not 523 and 525) were the same as those of the racemate (Essence/52). Example 53 Ν2-(4-(4-Ga-1HH1-yl)-3-methoxyphenyl)_ν4, Ν4-dimethyl-8-phenyl-7,8-dihydro-5Η-pyran [4,3-d]pyrimidine-2,4-diamine 149653.doc -376- 201107311

To 2-Chloro-indenyl-8-phenyl-7,8-di-argon-5/ί-pyrano[4,3-4 ° intimate-4-amine (135 mg, 0.466 mmol) and 4- (4-Ga-1/ί-i- sul-l-yl)- 3-methoxyaniline (104 mg, 0.466 mmol) in THF (1.0 mL) EtOAc (EtOAc) The reaction mixture was stirred at 75 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #-(4-(4- gas-1//-imidazol-1-yl)-3-decyloxyphenyl)-indole, #-dimethyl-8-phenyl-7. , 8-dihydro-5//-pyrano[4,3-&lt;1 pyrimidine-2,4-diamine butyl? Eight salts (80.1 mg, 0.130 mmol, yield 96%). LC-MS (M+H)+ = 477.3. NMR (500 MHz, CDC13) δ ppm 11.74 (1H, s), 7.74 (1Η, d, J=\.5 Hz), 7.36 (1H, s), 7.34-7.26 (6H, m), 7.15 (1H, d, J=8.2 Hz), 7.07 (1H, d, J=1.5 Hz), 4.83 (1H, m), 4.13-4.21 (1H, m), 3.81 (3H, s), 3.47 (3H, s), 3.32 (6H, s).

Examples 53A and 53B (S)-N2-(4-(4-Ga-1H-imidazole-l-yl)-3-f-oxyphenyl)-N4,N4-dimethyl-8-benyl- 7 , 8-dihydro-5H-pyrene and [4,3-d] bite-2,4-diamine and (R)-N2-(4-(4-chloro-1H-imidazolyl)-3 -Methoxyphenyl)-N4,N4-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4&gt;3_d]pyrimidine·2&gt;4_diamine 149653.doc • 377- 201107311

Purification #, (4-(4-chloro-1//-imidazo-bu)-3 methoxyphenyl)-#,#-dimercapto-8-phenyl-7, using a palmitic SFC, 8-Dihydro-5/f-pyrano[4U] °-densidine-2,4-diamine racemic mixture (go.! mg, 0.130 mmol) (f 53) 'Get peak A ( 21.2 mg, 0.044 mmol) (; T No peak B (24.2 mg, 0.051 mmol) (not 535). SFC method: Chiralpak OJ-H (3〇x250 mm, 5 μΜ) '35% sterol in C02 ( 0.1% diethylamine), 35 ° C, flow rate 70 mL / min, maintained for 13 minutes, 268 nm absorbance, injection of 5 μί 27 mg / mL solution in methanol (multiple stack injection), iR (peak A) = 4.5 min 'iR(peak Β)=9·5 min. The absolute stereochemistry of the individual enantiomers (Essence 535) was not determined. The lc_MS and 1H NMR analytical data and the elimination of the separated enantiomers The spirulina (actually not 53) is the same. Example 54 8-(4-Fluorophenyl)-indole 2-(3-methoxy-4-(3-f-yl-Hu〆-tris)]phenyl)- Ν4-mercapto-7,8-dihydro-5Η-piperido[4,3-d]. Bite-2,4

Prepare D (0.076 g, 0.38 mm 〇i) with argon at room temperature, make 149653.doc -378-201107311 preparation JaCO.ng, 0.38 mmol), Na2c〇3 (0.079 g, 0.75 mmol) And a solution of xantphos (0.216 g, 0.38 mmol) in two &quot;gasburn/water (9:1) for 1 hour. Pd(dba)3 (0.17 g '(Μ 8 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated under hydrazine for 24 hours. The reaction mass was passed through diatomaceous earth. The bed (Celite®) was filtered and washed with EtOAc (EtOAc)EtOAcEtOAcEtOAcEtOAcjjjjjjjjj The dried Na.sub.2SO.sub.sub.sub.sub.sub. 4-(3-indolyl-1H-1,2,4-triazol-l-yl)phenyl)_N4-methyl-7,8-dihydro-5H-pyrano[4,3-d] Pyrimidine

2,4-Iamine (0.08 g, 47%). LC-MS (M+H)+ = 462.2. Ifi NMR (400 MHz, DMSO-c/d): δ ppm 8.70 (1Η, s), 7.8 (1H, m), 7.5 (1H, m), 7.34 (2H, m), 7.21 (4H, m), 7.13 (1H, m), 4.60 (1H, d5 J=14.0 Hz), 4.46 (1H, d, 7=14.0 Hz), 3.83 (2H, m), 3-78 (1H, m), 3.75 (3H, s), 3.01 (3H, d, J = 4.0 Hz), 2.32 (3H, s5) 分离 separation of the racemic mixture by palm chromatography to give enantiomers 54A and 54B, both The same spectral data. Example 55 N4-Ethyl-8-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1'2,4-diin-1-yl)benzene基)_7,8-·一风-5H-派域弁[4,3-d] mouth bite · 2,4-diamine 149653.doc •379· 201107311

Prepare D (〇_〇85 g, 0.40 mmol), preparation Jb (0.16 g '0.52 mmol), Na2CO3 (0.11 g, 1.0 mmol) and xantphos (0.30 g, 0.52 mmol) with argon at room temperature ) Yu II. Solution in cacao/water (9:1) for 1 hour. Pd(dba)3 (0.26 g, 0.26 mmol) was added to the reaction mixture and the solution was again purged with a mixture of the mixture for one hour. The reaction mass was heated at 11 ° C for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (10 mL x 3). The organic layer was washed with a brine solution (10 mL) and dried over anhydrous Na.sub.4, and evaporated under reduced pressure to give a crude compound. The crude compound was purified by preparative HPLC to give N4-ethyl-8-(4-fluorophenyl)-N2-(3-decyloxy.4_(3-methyl-1H-1) as an off-white solid. 2,4-Diin-1-yl)phenyl)_7,8-dihydro-5H-pyrano[4,3_d]e-pyridine 2- 2,4-diamine (0.90^40 〇/.). 1^- PCT 8 (Inspection += 476.2. 丨11-face 11 (400 MHz, DMSO-c/&lt;5): δ ppm 8.69 (1H, s), 7 73 (1H s) 7.48 (1H, S) , 7.34 (2H, m), 7.21_7.13 (3H, m), 4 62 (iH, d, • 7 = 14.0 Hz), 4.47 (1H, d, */=14.0 Hz), 4·〇7 ( 2H, (4) 3 92 (2H, m), 3.82 (3H, s), 3.54 (3H, m), 2.33 (3H, s), i 22 (3H, t, / = 7.2.0 Hz). Separation of the racemic mixture by palm chromatography gave the enantiomer 149653.doc • 380·201107311 Examples 55A and 55B, both having the same spectral data example 56, (4-Q-1H-imidazole small group) )·3_Methoxyphenyl)_N4ethyl&(4-Phenylphenyl)-7,8-di-argon pentamidine[4&gt;3♦Midine-2-24 diamine

The preparation A (〇7〇g, 〇32 mm〇i), the preparation Jb (0.11 g, 〇·35 mm〇l), Na2C03 (〇.〇7 g, 071 mm) were purged with argon at room temperature. 〇1)

And a solution of xantphos (0.20 g, 0.35 mm 〇i) in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.18 g, 0.17 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated under 11 atmospheres for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (25 mL) dried over anhydrous Na.sub.2SO.sub. The crude compound was purified by preparative HPLC to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8 -(4-Fluorophenyl)-7,8-dihydro-5-N-[4,3-d] shouted -2,4-diamine (0.70 g, 40%). LC-MS (MH)+=495_2. 4 NMR (400 MHz, -DMSO-c/(5): δ ppm 9.91 (1H, sb), 7.83 (1H, m), 7.69 (1H, s),7· 39 (1H, s), 7·22 (4H, m), 7·10 (4H, m), 4.65 (1H, d, 149653.doc -381 - 201107311 J=14.0 Ηζ), 4·48 (1H, d, "/=14.0 Hz), 4.04 (1H, m), 3.83 (1H, m), 3.74 (3H, s), 3.54 (2H, m), 1.22 (3H, t5 7=7.2.0

Hz). Separation of the racemic mixture by palm chromatography gave the enantiomers. Both examples 56A and 56B&apos; had the same spectral data.

Example 57 A N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylfluorophenyl 4-((R)-3-fluoropyrrolidin-1-yl)-7, 8. Dihydro-5H-pyrano[4&gt;3_d]pyrimidine_ 2-m

Prepare A (〇〇51 g, 〇Μ mm〇1), preparation Jcl (0.09 g, 0.25 mmol), Na2C03 (0.050 g, 0.51 mmol) and xantphos (0.148 g, argon) at room temperature with argon. 0.25 mmol) of the solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (〇.l32 g, 0-12 mmol) was added to the reaction mixture and the resulting solution was again purged for one hour. The reaction mass was heated for 1 hour under a 丨〇 (&gt;c. The reaction material was filtered over a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with aq. EtOAc (EtOAc) (EtOAc) (EtOAc) 〇 〇 〇 〇 , , , 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 纯化 纯化 〇 〇 纯化 纯化 纯化 纯化 纯化_3_曱oxyphenyl)_8-(4_fluorophenyl)_4_((R)-3-fluoroindolepyrazine-丨·yl)_7,8_dioxin_5H_pyrano[4, 3_d]pyrimidine_2_amine (0.030 g, 18〇/0) 〇LC-MS (Μ+Η)+=539·0. 4 NMR (400 MHz, DMSO·^): δ PPm 9.19 (1H, s), 7.89 (1H, s), 7.74 (1H, s), 7.43 (1H, s), 7-27 (2H, m), 7.18-7.11 (4H, m), 5.42 (1H, m), 5.04 (1H, Ds */=13.6 Hz), 4.81 (1H, d, J=13.6 Hz), 4.13 (2H, m), 3.91-3.77 (4H, m), 3.66 (1H, m), 3.58 (3H, s), 2.23 (2H, m) 〇Example 5ΊΒ N-(4-(4- -1H-imidazol-1-yl&gt; 3-methoxyphenyl)-8-(4-fluorophenyl)-4_((R)-3-fluoropyrrolidin-1-yl)-7,8- Dihydro-5H-piperazino[4,3-d]pyrimidine-anthracene-amine

Prepare A (〇.〇 62 g, 0.28 mmol), preparation Jc2 (0.110 g '0.31 mmol), Na2CO3 (0.066 g, 0.62 mmol) and xantphos (0.181 g, 0.31 mmol) with argon at room temperature A solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.162 g, 0.15 mmol) was added to the reaction 149653.doc -383 - 201107311 mixture and the resulting solution was purged with argon for an hour. The reaction mass was heated under UGt for 24 hours. The reaction mixture was filtered through a pad of Celite (Celhe) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (50 mL×2). The combined organic layers were dried over EtOAc EtOAc (EtOAc) elute The crude compound gave N-(4-(4-H-1H-imidazol-1-yl)-3-yloxyphenyl)-8(4-fluorophenyl)-4-((R)- 3-fluoropyrrolidine 丨 基 基 _ _ , , , 4 4 4 4 4 4 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 胺 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ )+=539·0. Nmr (400 MHz, DMSO-must): § ppm 9.21 (1H, s), 7.87 (1H s) 7·74 (1H, s), 7.43 (1H, s), 7.24 (2H , m), 7.16-7.09 (4H m) 5.36 (1H, m), 4·95 (2H, m), 5.05 (1H, m), 3.95-3.80 (2H m), 3.78-3.70 (4H, m) , 3.6 (3H, s), 2.22 (2H, m).

Example 58A N-(4-(4-Chloro-1H-imidazolyl)_3_methoxyphenyl)_8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidinyl)_7,8 —Dihydro·5H_pyrano[4j_d]pyrimidine 2-amine

149653.doc -384 · 201107311 Preparation of A (〇〇57 g, 〇28 mm〇l), preparation Jdl (0.10 g '0.28 mmol), Na2C03 (0.06 g, 0.56 mmol) with argon at room temperature And xantphos (0.16 g, 0.28 mmol) in dioxo/water (9:1) for 1 hour. Pd(dba)3 ((M4 g, 〇, 14 mm〇1) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at rc1 (rc) for 24 hours. The mixture was filtered with EtOAc (EtOAc) (EtOAc) The organic layer was dried over anhydrous Naj.sub.4, and evaporated. N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_8_(4-_phenylphenyl)4_((S)·3-fluoropyrrolidine as an off-white solid _丨·基)_7,8_Dihydro_SH piperazo[4,3_d]pyrimidine_2_amine (0.040 g, 27%). LC_MS (M+H)+=539 〇.lH nmr (4〇〇 MHz, DMSO-^): δ ppm 9.45 (1Η, sb), 7.79 (1Η, s), 7.71 # ^ 7-47 (1H, s), 7.34-7.26 (2H, m), 7.21-7.12 (4H, m), 5.41 (1H, m), 5.07 (1H, d, J = 14.0 Hz), 4.85 (1H, d, ^=14.0 Hz), 4.53-4.38 (2H, m)5 4.32-4.30 (4 H, m), 3.89- 3.64 (4H, m), 2.50-2.58 (2H, m).

Example 58B N-(4-(4-chloro-1H-imidazol-1-ylmethoxyphenyl 2 amide) I49653.doc •385 - 201107311

F Purified preparation A (〇.062 g, 0.282 mmol), preparation Jd2 (0.11 g, 0.310 mm〇l), Na2C〇3 (〇.065 g, 0.620 mmol) and xantphos with argon at room temperature. (0.179 g, 0.310 mmol) in a solution of dioxane/water (9:1) for 1 hour. Pd(dba)3 (0.16 g, 0.155 mmol) was added to the reaction mixture and the resulting solution was again purged for a few hours. The reaction mass was heated at u 〇 ° c for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (2 mL EtOAc) The crude compound was purified by column chromatography (60420 mesh) using a dioxane hydrazine solution of 1% decyl alcohol as a mobile phase to give N-(4-(4-H-1H-imidazole) as an off-white solid. -1-yl)-3-decyloxyphenyl)_8_(4-fluorophenyl)4-((S)-3-fluoropyrene η each bite_1_yl)_7,8-dihydro-5H- D South and [4,3-d]»Midine-2-amine (0_040 g, 27%). LC-MS (Μ+Η)+=539·〇.咕NMr (400 MHz, DMSO-must): δ ppm 9.39 (1H, s6), 7.78 (1H, s), 7.71 (1H, m), 7.46 (1H, s), 7.28-7.13 (6H, m), 5.40 (1H, m), 4.94 (2H, m), 4.04-3.95 (4H, m)5 3.83 (3H, m), 3.67 (3H, m), 2.33_2·〇8 (2H, m). Example 59 149653.doc -386- 201107311 N4-^S-N2-(3-M-4-(5- ^ 1 Η-1,2,4- = 1 - Μ) ^ M)~ 8-(4- Fluorophenyl)-7,8-dihydro-5H-piperidinopyrimidine-24-diamine

F φ Combine Preparation C with Preparation Jb using the method of Example 56 to obtain N4-B.

-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-tris. sitting_ι_yl)phenyl)_8_(4-fluorophenyl)-7,8-dihydro -5H-pyrano[4,3-d]pyrimidine-2,4-diamine. LC-MS (M+H)+=464.3 JHNMR (500 MHZ,Me〇D)SPpm7.99- 8.06 (2H, m), 7.24-7.34 (4H, m), 7.〇4 (2 Η, t, J=8.70 Hz), 4.65 (1 H, d, J=14.30 Hz), 4.56 (1 H, d, */= 14.30 Hz), 4.16 (1 H, dd, “7=11.29, 4.58 Hz) , 3.94-4.00 (1 H, m), 3.92 (1 H, t, /=4.88 Hz), 3.57 (2 H, q, J=7.12 Hz), 2.37 (3 H, s), 1.29 # (3 H , t, / = 7.17 Hz). Separation of the racemic mixture by palm chromatography gave the enantiomers. Examples 59A and 59B&apos; had the same spectral data. Example 60 N2-(4-(4-虱-lH-o m. sit-1-yl,-3-methoxyphenyl)-cedar-(4-fluorophenyl)-N4-methyl-7, 8-Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine 149653.doc -387· 201107311

Preparation A (0.15 g, 〇61 mm〇1), preparation Ja (0·20 g, 〇·61 mm.1), Na2C〇3 (〇.i44 g, 1.31) were purged with argon at room temperature. Mm〇1) and Xantph〇S (0.39 g, 〇61 mm〇1) in a solution of dioxane/water (9:1) 1 J, add Pd(dba)3 (〇.31 g, 0.32 mmol) The resulting solution was rinsed into the reaction mixture for an additional hour. The reaction mixture was heated at EtOAc (25 mL EtOAc). Aqueous solution. The combined organic layers were washed with brine (25 mL) and dried over anhydrous Na.sub.2SO.sub.sub.sub. The petroleum ether solution of ethyl acetate is used as the mobile phase to purify the crude compound 9 solid-gas-...-yl)·oxy 2:fluorophenyl)-N4-mercapto-7,8_dioxin_5H_ Piperazo[4,3_d]pyrimidine heart, anal diamine (0.12 g, 37%). LC_MS (M_H)+=479 〇.1h position (complete MHz, DMSO-^): δ ppm 12 〇2 (1Η) S6)} 9 17 (ιη^ g 〇6 ^ 7.73 (1Η&gt; s), 7.41 (1Η, s), 7.25-7.08 (5Η, m), 6.77 〇Η, m), 4.57 (1H, d5 y=14.4 Hz), 4.44 (1H, d, /=14.4 Ηζ)? 4-02 (1H, m), 3.89 (1H&gt; m), 3.80 (1H, m), 3.3 (3H, s), 2.93 (3H,d , J=4.〇Hz). 'Enantiomers are obtained by separating the racemic mixture by palm chromatography. 149653.doc 201107311 Examples 60A and 60B 'Two Having the same spectral data. Example 61 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-]^4" 4-dimethyl-7,8-dihydro-5}\-pyrano[4,3_1]pyrimidine-2,4-

Prepare A (0.15 g, 0.70 mmol), Prepare Je (0.24 g, 0.78 mmol), Na2CO3 (0.16 g, 1.56 mmol) and xantphos (0.45 g, 0.78 mmol) in argon at room temperature Hmm the solution in the water/water (9:1) for 1 hour. Pd(dba)3 (0.35 g' 〇 _39 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 110 ° C for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with a brine solution (2 mL), dried over anhydrous Na? The crude compound was purified by Combiflash (2 g, EtOAc, EtOAc (EtOAc): -1-base)_3_methoxy phenyl)_8_

2,4-Diamine (0.15 g, 47%). - Diamine (0.15 g, 47%). LC-MS (Μ-Η)+=493·〇. 1 =493.0 〇iH nmr 149653.doc •389· 201107311 (400 MHz, DMSO-c/&lt;5): δ pPm 9.21 (1H, s), 7.9] (iH, s), 7.73 (1H, s), 7.41 (1H, s), 7·24 (2H, m), 7·14 (4H, m), 4.83 (1H, d, J = 13.6 Hz), 4.70 (1H, d, J = 13.6 Hz), 4.16 (ih, m), 4.10 (1H, m), 3·72 (1H, m), 3.56 (3H, s), 3.06 (6H, s). Separation of the racemic mixture by palm chromatography gave enantiomers Examples 61A and 61B, both having the same spectral data. Example 62 N2-(4-(4- gas-1H-methanol.sodium-1-yl)-3-methoxyphenyl)-indole 4-ethyl-8. (4-air-based)-Ν4-ψ Base - 7,8-dioxin - 5Η-^α南和[4,3-d] 喷 bit_2 4

Prepare A (0.13 g, 0.61 mmol), preparation Jf (0.20 g, 〇·61 mmol), Na2CO3 (0,13 g, 1.2 mmol) and xantphos (0-36 g, 0.61) with argon at room temperature Methyl) solution in dioxane/water (9:1) and hours. Pd(dba)3 (0.28 g, 0.3 1 mmol) was added to the reaction mixture and the resulting solution was again purged for one hour. The reaction mass was heated at 11 (rCT) for 24 hours. The reaction mixture was filtered over a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced room and the residue was diluted with water. extracted with ethyl acetate (30 mL) The combined organic layer was washed with brine (2 mL), dried over anhydrous EtOAc EtOAc EtOAc EtOAc EtOAc. g), the crude compound is purified using a petroleum ether solution of 5% ethyl acetate as a mobile phase to give N2-(4-(4-chloro-1H-imidazolyl) , N4, ethyl-8-(4-fluorophenyl)·Ν4_methyl-7,8-dihydro-5H-pyrano[4,3-pyrimidine-2,4-diamine (0.097 g, 47%) ) LC-MS (Μ+Η)+=509·2. 4

NMR (400 MHz, DMSO-〇?6): δ ppm 9.17 (1H, s), 7.83 (lH s), 7.72 (1H, s), 7.40 (1H, s), 7.24 (2H, m), 7.12 ( 4H,m) • 4 78 (!Η, d, J=13.6 Hz), 4.65 (1H, d, J=13.6 Hz), 4.09 (lH m), 3.73 (1H, m), 3.55 (1H, m) , 3.54 (3H, s), 3.38 (2H, 3.02 (3H, s), 1.20 (3H, t, /=6.9.0 Hz). Separation of the racemic mixture by palm chromatography Isomers Examples 62A and 62B, both have the same spectral data. Example 63 N-(4-(4-Chloro-1H-imidazole-:yl)-methoxyphenyl)_4_(3,3 Fluoroazetidin-1-yl)-8-(4-fluorophenyl γ7&gt;8-dihydro-5H-pyrano# °-mididine-2-amine

Prepare A (0.082 g, 0.31 mmol), preparation Jg (0.13 g, 0.31 mmol), Na2C〇3 (〇.〇 77 g, 〇72 mm〇i) with argon at room temperature 149653.doc • 391 - 201107311 and xantphos (0.21 g, 〇_31 mmol) in dioxo/water (9:1) for 1 hour. Pd(dba)3 (0.16 g, 0.12 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 11 ° C for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (30 mL &gt;&lt; 2). The combined organic layers were washed with a brine solution (2 mL) and dried over anhydrous Na.sub.2.sub.4, and evaporated under reduced pressure to afford crude compound. The crude compound was purified by Combiflash (20 g) using a 50% ethyl acetate ethyl ether petroleum solvent as mobile phase to afford N-(4-(4-chloro-1H-imidazole) as an off-white solid. 1-yl)-3-fluorenyloxyphenyl)_4_(3,3_-fluoroazepine-butyl-1-yl)-8-(4-fluorophenyl)-7,8-dihydro-51^ - Deutero[4,3-d]pyrimidin-2-amine (0.070 g, 35%). LC-MS (M-H)+ = 541.0. Towel NMR (400 MHz, DMSO-dosed): δ ppm 9.41 (1H s) 7.88 (lH, s), 7.73 (lH, s), 7.41 (lH, s), 7.25 (2H, m), 7.17_7.08 ( 4H, m), 4.78-4.63 (6H, m), 4.04 (2H, m), 3 78 (1H, m), 3·50 (3H, s). Separation of the racemic mixture by palm chromatography gave the enantiomers Examples 63A and 63B, both having the same spectral data. Example 64 N2-(4-(4-Ga-1H-imidazo-i-yl)-3-methoxyphenyl)_8-(4-phenylphenyl)_N4-methyl-7,8-dihydro·5H • piperido[4,3-d]pyrimidine_2&gt;4_diamine 149653.doc -392· 201107311

According to the combination of Shihe 26, 2-gas-8-(4-phenylphenyl)-N-mercapto-7,8-dihydro-5H-0, 0-Nan[4,3_d]pyrimidine-4-amine (#潆Do not ") (116 mg, 0.374 mmol) and 4-(4-gas-1H-imidazol-1-yl)_3-decyloxyaniline (shoulder/潆#)) (84 mg, 0.374 mmol) and purified ' Obtained n2_(4-(4-chloro-1H-i-pyran-1-yl)-3-indolyloxyphenyl)-8-(4-phenylphenyl)-N4-indolyl-7 as a white solid , 8-Dihydro-5H-p-pyrano[4,3-d]pyrimidine-2,4-diamine TFA salt (105 mg, 0.172 mmol, yield 45.9%). LC-MS (Μ+Η)+=497·1. NMR (5 00 MHz, MeOD) δ ppm 7.86 (1 Η, br. s.), 7.63 (1 H, br. s.), 7.30-7.46 (6 H, m), 7.19 (1 H, dd, 7 =8.55, 2.14 Hz), 4.62-4.73 (1 H, m), 4.56 (1 H, d, 7=14.65 Hz), 4.11-4.20 (1 H, m), 4.07 (1 H, d, /=3.36 Hz), 3.94 (1 H, dd, /=11.44, 3.81 Hz), 3.82-3.89 (3 H, m), 3.10-3.20 (3 H, m)=

Example 64 A N2-(4-(4-Chloro-1H-imidazole-l-yl)-3-methoxyphenyl μ8_(4_ phenylphenyl hydrazine-methyl, each - 虱-511-pyran And [4&gt;3-(1]° bite-2,4-diamine

149653.doc •393· 201107311 Separation of Ν2-(4-(4-气-ΐΗ-imidazole-A) by multiple injections of palm HPLC (OJ-H 30x250 mm, 10 μΜ, 35% EtOH/hexane) Oxyphenyl)-8-(4-(phenyl)-N-indolyl-7,8-dihydro-55-pyrano[4,3-d]pyrimidine-2,4-diamine实天/&lt;^), gave 2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chloro) as an off-white solid Phenyl)-N4-mercapto-7,8-dihydro-511-pyrano[4,3-pyrimidine-2,4-diamine butyl? octahydrate (first eluted, enantiomer A (3 5 mg, 0.057 mmol) LC-MS (M+H)+= 497.1 〇'Η NMR (500 MHz, MeOD) δ ppm 7.80 (1 Η, s), 7.71 (1 Η, s), 7.36 (2 Η, d, /=8.24 Hz), 7.25-7.30 (3 H, m), 7.22 (1 H, d, 7=8.55 Hz), 7.03 (1 H, d, 7=8.55 Hz), 4.50- 4.68 (2 H, m), 4.15 (1 H, dd, J=11.29, 4.27 Hz), 3.97 (1 H, t, /=4.27 Hz), 3.87-3.94 (1 H, m), 3.66 (3 H , s), 3.08 (3 H, s). The absolute stereochemistry of the fate was not determined.

Example 64B N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N4-methyl-7,8-di Hydrogen-5H-pyrano[4,3-d]pyrimidine-2,4-diamine

Separation of Ν2-(4-(4-chloro-1Η-imidazol-1-yl)-3-indole by multiple injections of palm HPLC (OJ-H 30x250 mm, 10 μΜ, 35% EtOH/hexane) Oxyphenyl)-8-(4-chlorophenyl)-N4-mercapto-7,8-dihydro-5H-pyrano[4,3-d] 149653.doc - 394· 201107311

Pyrimidine-2,4-diamine (n.1) gave n2_(4_(4_chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_8_(4_chloro) as an off-white solid Phenyl)·ν4_methyl-7,8-di-argon-5Η-pyrano[4,3-d]pyrimidine-2,4-diamine TFA salt (second elution of 'enantiomers' B) (29 mg, 0.047 mmol). LC-MS (M+H)+=497.1 〇»Η NMR (500 MHz, MeOD) δ ppm 7.78 (1 Η, s), 7.72 (1 Η, d, J=1.53 Hz), 7.34-7.39 (2 H , m), 7.26-7.31 (3 H, m), 7.24 (1 H, d, /=8.55 Hz), 7.04 (1 H, dd, J=8.55, 2.14 Hz), 4.51-4.68 (2 H, m ), 4.15 (1 H, dd, 7=11.29, 4.58 Hz), 3.98 (1 H, t, J=4.43 Hz), 3.91 (1 H, dd, •7=11.44, 4_73 Hz), 3.68 (3 H , s), 3.09 (3 H, s). The absolute stereochemistry of f is not determined. Example 65

N2-(4-(4-Ga-1H-Mimi. Sodium methoxyphenyl) Winter (4-H-Phenyl) to 1,4-Dimethyl-7,8-dihydro-51{ - Trace and [4}34] 0 〇 〇 _2, 4 _ diamine CI

According to the real / / / 26 combination 2_ chloro _8_ (4 _ phenyl) _ N, N 曱 曱 _7,8 · dihydro-5H-pyrano[4'3-d] blasting _4 _amine (agricultural squad called (125 mail, 〇38 匪.1) and 4·(4·qiqin (tetra)·1·yl)·3-methoxyaniline (I oblique mg, 0. 〇mm〇l) and Purification afforded Ν2_(4_(4 chloro-m+m)~oxyphenyl from (4_ phenyl)_ν4, ν4• 〒 149653.doc •395 201107311 -7,8- Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (110 mg, 0.176 mmol, yield 45.6%). LC-MS (M+H)+=5 11 · 1. 'ΗΝΜΙΐρΟΟΜΗζ,ΜβΟΓΟδρριη?”!^!!,!^^.),?.〗 〖 7.51 (7 H, m), 7.16 (1 Η, dd, J=8.39, 1.98 Hz), 4.91-5.05 (2 H, m), 4.12-4.30 (2 H, m), 3.76-3.91 (4 H, m), 3.34-3.44 (6 H, m).

Example 65 A N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)-N4,N4-dimethyl-7 ,8-Dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine

Separation of Ν2-(4-(4-Ga-1Η-imidazol-1-yl)-3 by multiple injections of palm HPLC (OJ-H 30x250 mm, 10 μΜ, 35 ° / 〇 EtOH / hexane) -decyloxyphenyl)-8-(4-chlorophenyl)-N4,N4-dimercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4 -Diamine (Real Hungarian &lt;55) gave N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4- Phenyl phenyl)-N,N - fluorenyl-7,8-dihydro-5H-pie. Nanhe [4,3-(1] mouth bite-2,4-diamine TFA salt (first eluted out of 'enantiomer eight) (35 mg, 0.056 mmol). LC-MS (M+H)+ = 511.1 〇'H NMR (500 MHz, MeOD) δ ppm 7.71 (1 H, d, /=1.22 Hz), 7.67 (1 H, s), 7.36 (2 H, d, /=8.55 Hz), 7.24- 7.30 (3 H, m), 7.22 (1 H, d, 7=8.55 Hz), 7.01 (1 149653.doc -396- 201107311 H, dd, /=8.55, 2.14 Hz), 4.77-4.96 (2 H, m), 4.23 (1 H, dd, «/=11.44, 5.65 Hz), 4.11 (1 H,t,/=5.65 Hz), 3.84 (1 H,dd, J=11.60, 6.10 Hz), 3.60-3.66 (3 H, m), 3.18-3.23 (6 H, m) _. The absolute stereochemistry of the 1st/65J was not measured.

Example 65B N2-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxyphenyl)-8-(4-chlorophenyl)-, 1^4-dimethyl- 7,8-Dihydro-51{-〇 喃 [ [4,3-(^ cancer bite-2,4-diamine

Separation of Ν2-(4-(4-气-1Η-imidazol-1-yl)-3- by multiple injections of palm HPLC (OJ-H 30x250 mm, 10 μΜ, 3 5% EtOH/hexane)曱oxyphenyl)-8-(4-phenylphenyl)-N4,N4-dimethyl-7,8-dihydro-5H-pyrano[4,3-(1]pyrimidine-2,4 -diamine (real 1 you 65)' is obtained as an off-white solid]^2_(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4- Chlorophenyl)-N4,N4-dimethyl-7,8-dihydro-5H-piperazo[4,3-d]pyrimidine-2,4-diamine TFA salt (second elution, right </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 1 H, s), 7.38 (2 H, d, /=8.55 Hz), 7.22-7.33 (4 H, m), 7.03 (1 H, dd, /=8.55, 2.14 Hz), 4.81-4.97 (2 H , m), 4.24 (1 H, dd, /=11.44, 5.65 Hz), 4.13 (1 H, t, 7=5.49 Hz), 3.85 (1 H, dd, 149653.doc •397- 201107311 J=ll_44, 5.95 Hz), 3.68 (3 H, s), 3·24 (6 H, s). Not determined f (absolute stereochemistry of 55 。. Example 66 Ν-(4-(4-chloro-1Η-imidazole-1) -ylmethoxyphenyl)_8_(4-chlorophenyl)_ 4-(3,3--azacyclobutan-1-yl)-7,8-di %^-5Η-派喃和痛啶-2-amine

According to the combination of 2 and 5; 2-gas-8-(4-phenylphenyl)-4-(3,3-dioxaazetidin-1-yl)-7,8-dihydro-5Η- Piperaco[4,3-d]pyrimidine (agricultural scorpion phantom (125 mg, 0.336 mmol) and 4-(4-chloro-1H-imidazol-1-yl)_3-methoxyaniline (袅#) d) (75 mg, 0.336 mmol) and purified to give N-(4-(4-H-1H-M.s.). _ gas phenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-d benzo[4,3_d] 〇密 bit-2 -Amine TFA salt (40 mg, 0.059 mmol, yield 1769%). LC-MS ( Μ + Η) + = 559·1. NMR (500 MHz, δ ppm 7.83 (1 H, br. s.), 7.39 -7.45 (3 H,m), 7.31-7.39 (4 H,m), 7.17 (1 H, dd, J=8.55, 2.14 Hz), 4.88-4.97 (5 H, m), 4.74- 4.81 (1 H , m), 4.08-4.19 (2 H, m), 3.91 (1 H, dd, 7=11.44, 3.81 Hz), 3.81 (3 H, s) 149653.doc -398 - 201107311

Example 66A N-(4-(4-H-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-chlorophenyl)_

4-(3,3-difluoroazetidin-indenyl)-7,8-dihydro-5H-pyrano[4,3-dJ-pyridin-2-amine

Separation of Ν-(4-(4-chloro-1Η-imilyl)-3 by multiple injections of palmitic SFC (OD-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) -nonyloxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5Η-pyrano [4,3-d]pyrimidin-2-amine (Nilute/Μ) gave N-(4-(4-H-1H-imidazol-1-yl)-3-methoxy Base)_ 8-(4-chlorophenyl)-4-(3,3-dioxazepine-1-yl)_7,8_dioxin-5H_ 0 bottom shout and [4,3-( !]&quot;Bite-2-amine (first eluted, enantiomer VIII) (7.8 mg '0.014 mmol). LC-MS (M+H)+=559.1. NMR (500 MHz, MeOD) δ Ppm 7.76 (1 H, s), 7.66 (1 H, s), 7.31 (2 Η, d, J=8.24 Hz), 7.20-7.27 (3 H, m), 7.10-7.16 (1Ή, m), 6.97 (1 H, d, 7=8.55 Hz), 4.68-4.83 (2 H, m), 4.55-4.66 (4 H, m), 4.16 (1 H, dd, "7=11.44, 5.04 Hz), 4.02 ( 1 H,t,*7=4.88 Hz), 3·88 (1 H,dd,*7=11.29, 5.80 Hz), 3.49 (3 H,s) » Absolute stereochemistry not determined.

Example 66B 149653.doc -399· 201107311 Ν-(4-(4-Μ,-ΙΗ- f-^ΜΜΜ)-8-(4 4-(3,3-a gas-gas hetero-f butyl ketone-1-yl )-7,8-二风-51~1- slightly v-nan[4,3-d] pyridine-2-amine

Separation of Ν-(4-(4-Ga-1Η-imidazol-1-yl) by multiple injections of palmitic SFC (OD-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) 3-methoxyphenyl)-8-(4-phenylphenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5H-piperidin N-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxy group as a white solid, m.p. [4,3-d]pyrimidin-2-amine Phenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-5 H-pyrano[4, 3-d]pyrimidin-2-amine (second elution, enantiomer B) (8.1 mg, 0.014 mmol). LC-MS (Μ+Η)+=559·1. NMR (5 〇〇 MHz, MeOD) δ ppm 7.76 (1 H, d, J = 2.14 Hz), Ί .61 (1 H, d, 7 = 1.53 Hz), 7.29-7.34 (2 H, m), 7.19 -7.27 (3 H, m), 7.13 (i H, d, J=8.55 Hz), 6.97 (1 H, dd, /=8.55, 2.14 Hz), 4.67. 4.84 (2 H, m), 4.60 (4 H,t,"7=12.21 Hz), 4.17 (1, H, dd 7=11.44, 5.04 Hz), 4.02 (1 H, t, /=5.19 Hz), 3.88 (1 Hs dd 7=11.29, 5.80 Hz ), 3.46-3.51 (3 H, m). Absolute stereochemistry not determined. Example 67 149653.doc -400- 201107311 8-(4-Chlorophenyl)-N2-(3-fluoro-4-(5-phenyl)-N4,N4-dimethyl-7,8-f- Indole-1,2,4-triazol-1-yl)monohydro-5H-piperidino[4 3d-pyrimidine_

2,4_ diamine

According to the actual / / / 26 combination 2- gas-8-(4-chlorophenyl)_N, N• dimethyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-4 -amine (chicken #心) (128 mg, 〇395 _〇1) and 3 preparations 4-(5-methylxian-10-2, triterpenoid) aniline (Agriculture (4) C) (76 mg, 0.395 mmol) And purify to give 8(4·gasphenyl)-N2-(3-fluoro-4-(5-fluorenyl-also-cardiotriazole)phenyl)_N,N4· as a white solid. Dimethyl-7,8-dihydro-5H-piperacino[4,3-d]pyrimidine·2,4·diamine TFA salt (120 mg, 0.202 mmol, yield 51.2%). LC_MS (μ+η)+= 480.1 〇NMR (500 MHz, MeOD) δ ppm 8.07 (1 hs) 7.80 (1 H, dd, 7=12.36, 2.29 Hz), 7.54 (1 H, t, J=8.55 Hz ), 7.40-7.47 (3 H,m),7.34-7.40 (2 H,m),4.90-5.04 (2 H,m)' 4.22-4.28 (1 H,m), 4.20 (1 H,br· s .), 3.87 (1 H, 7 = 11.44, 5.34 Hz), 3.39 (6 H, s), 2.40 (3 H, s). ’

Example 67 A 8-(4-Chlorophenyl)-N2-(3-fluoro-4-(5-gas Uh-12 4-tri---yl)phenyl)-N4,N4-dimethyl- 7,8-Dihydro-5H-pyrano[4,3_d]pyrimidine·]4 Diamine I49653.doc -401 - 201107311

Separation of 8-(4-chlorophenyl)-#-(3-fluoro-4 by multiple injections of palmitic SFC (AD-H 30x250 mm '5 μΜ, 40% MeOH (0.1% DEA)/C02) -(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,N4-dimercapto-7,8-dihydro-5H-pyrano[4,3 -d]pyrimidine-2,4-diamine (real / / #7) 'Get 8-(4-hydroxyphenyl)-N2-(3-fluoro-4-(5-fluorenyl)- in opaque glass 1H-1,2,4-triazol-1-yl)phenyl)-N4,N4-dimethyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2, 4-Diamine (first eluted, enantiomer A) (25.8 mg, 0.054 mmol) ° LC-MS (Μ+Η)+=480.1 ° *Η NMR (400 MHz, MeOD)

δ ppm 7.99 (1 Η, s), 7.87-7.95 (1 Η, m), 7.19-7.33 (6 Η, m), 4.72-4.83 (2 Η, m), 4.22 (1 Η, dd, 7=11.33 , 5.54 Hz), 4.02 (1 Η, t, /=5.67 Hz), 3.87-3.95 (1 Η, m), 3.09 (6 Η, s), 2.33 (3 Η, s). The absolute stereochemistry of the solid fraction / 674 was not determined. Example 67B 8-(4-Chlorophenyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazole·i 臬)phenyl)-N4,N4-di Methyl-7,8-dihydro-5H-pyrynan [4,3-d]pyrimidine_2,4_-amine 149653.doc -402- 201107311

Separation of 8-(4-chlorophenyl)-1^2-(3-fluoro) by multiple injections of palmitic SFC (AD-H 30x250 mm, 5 μΜ, 40% MeOH (0.1% DEA)/C02) 4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,N4-dimercapto-7,8-dihydro-5H-pyrano[4 , 3-d]pyrimidine-2,4-diamine (actually ^7), which gives 8-(4-hydroxyphenyl)-N2-(3-fluoro-4-(5-methyl) as an opaque glass -1H-1,2,4-tris(yt-1-yl)phenyl)-N4,N4-dimethyl-7,8-dihydro-5H- bottom. Nanhe [4,3-d] pyridine-2,4-diamine (second elution, enantiomer b) (25.8 mg, 0-054 mmol). LC-MS (M+H)+=48 〇 1. Ijj NMR (400 MHz,

MeOD) δ ppm 7.99 (1 H, s), 7.87-7.94 (1 H, m), 7.20-7.31 (6 H, m), 4.72-4.84 (2 H, m), 4,22 〇H, Seto U 33, 5 54 Hz), 4. 〇 2 (1H, W79Hz), 3.92 (1Hddj=ii 33 6 〇4 call, 3.〇9(6^), 2-33 (3^. Not determined) Qingzhi Absolute stereochemistry. Example 68 Guanglaji II I氡 miscellaneous yield% y tiger year old-heart (5-methyl-1H-1,2,4-triazol-1-yl)-7,8-two Hydrogen-5H-派.南和[4&gt;d]. Condensation, 2, amine 149653.doc -403« 201107311

According to the actual combination of 26, 2-gas-8-(4-phenylphenyl)-4-(3,3-diacetohydrocyclobutan-1-yl)-7,8-dihydro-5H-pyran And [4,3-d]pyrimidine (袅余面心^(128 mg, 0.344 mmol) and 3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-bu)aniline (Nongguang #C) (66.1 mg '0_344 mmol) and purified to give 8-(4-phenylphenyl)-4-(3,3-difluoroazetidin) base as a white solid. N_(3_^-4-(5-methyl-1H-1,2,4-disial-1-yl)benyl)-7,8-dihydro-5ΗΗηη[4,3-d]pyrimidine 2-Amine TFA salt (120 mg, 〇.187 mm 〇1, yield 54.4%). LC-MS (M+H) -528.1 NMR (500 MHz,

MeOD) δ ppm 8.01-8.10 (1 Η, m), 7.75-7.85 (1 Η, m) 7 25-7.50 (6 Η, m), 4.70-4.96 (6 Η, m), 4.13-4.24 (1 Η , m) 4 02- 4.13 (1 Η, m), 3.96 (1 Η, dd, /=11.44, 4.73 Hz), 2.32-2.44 (3 Η, m) ° Example 69 8-(4-chlorophenyl) ^_(3_Fluoro_4_(5_methyl·1Ηΐ24三峻小基)phenyl)-Μ·methyl·7,8-dihydro-5Η•piperidinopyrimidinediamine 149653.doc -404· 201107311

According to: combination 2-chloro-8-(4-phenylphenyl)-N-mercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (farm farm ") (150 mg, 0.484 mmol) with 3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)aniline (infested c) (9; 3 mg, 0.484 mmol) and purified to give 8-(4-chlorophenyl)-like-(3-fluoro-4-(5-methyl-1^1-1,2,4-three)&gt; in a clear, colorless glass. -1--1-yl)phenyl)-1^4-mercapto-7,8-dihydro-511-(1 benzo[4,3-(1]ming"--2,4-diamine八八盐(120 mg, 0.207 mmol, yield 42.8%). LC-MS (M+H)+= 466.1.]H NMR (500 MHz, Me〇D) δ ppm 8.08 (1 Η, s), 7.89 -7.96 (1 Η, m), 7.57 (1 Η, t, J=8.55 Hz), 7.47-7.52 (1 H, m), 7.42-7.46 (2 H, m), 7.34-7.40 (2 H, m ), 4.53-4.74 (2 H, m),

4.18 (1 H, dd, "7=11.44, 4.43 Hz), 4.07-4.13 (1 H, m), 3.95 (1 H, dd, /=11.44, 4.12 Hz), 3.17 (3 H, s), 2.42 (3 H, s). Example 69 A 8-(4-Chlorophenyl)-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-A Base-7,8-dihydro-5H-bromo-[4,3-d] mouth bite-2,4-diamine

149653.doc •405- 201107311 Separation of 8-(4-phenylphenyl)-:^ by multiple injections of palmar SFC (AD-H 30x250 mm, 5 μΜ, 201⁄4 MeOH (0.1% DEA)/C02) -(3-Fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-indolyl-7,8-dihydro-5Η·pipelan [4,3-d]pyrimidine-2,4-diamine (not 69) gave 8-(4-phenylphenyl)-v2-(3-fluoro-4-(5-methyl) as a white solid. -1Η-1,2,4-triazol-1-yl)phenyl)-indole 4-methyl-7,8-dihydro-5-pyrido[4,3-d]pyrimidine_2,4· Diamine (first eluted, enantiomer A) (5 2.4 mg, 0.112 mmol). LC-MS (Μ+^^Αόό.Ιο^ΝΜΙΐρΟΟΜΗζ,ΜβΟΖ^δρριη?”?- 8.13 (2 H, m), 7.17-7.41 (6 Η, m), 4.48-4.72 (2 Η, m), 4.17 (1 Η, dd, J=11.29, 4.58 Hz), 3.98 (1 H, dd, J=11.44, 5.04 Hz), 3.93 (1 H, d, J=4.88 Hz), 2.99-3.08 (3 H, m ), 2.35-2·42 (3 H, m). The absolute stereochemistry of the test is not measured.

Example 69B 8~(4-Chlorophenyl)-N2-(3-fluoro-4-(5-carbyl-111-1,2,4-tris-l-yl)phenyl)-N-A -7,8-diaza-5H-jal-[4,3-d] succinyl-2,4-diamine

Separation of 8-(4_chlorophenyl)_Ν2_(3·说·4_() by multiple injections of palmar SFC (AD-H 30x250 mm, 5 μΜ, 20% Me〇H (0.1% DEA)/C02) 5_ 曱yl_1Η-1,2,4-triazol-1-yl)phenyl)_Ν4_methyl_7,8_ dihydro_5Η·Pheno[4,3-d]pyrimidine-2,4- Diamine (real / lux / 69), obtained as a white solid 149653.doc • 406-201107311 8-(4-chlorophenyl)_N2_(3_fluoro_4_(5_methyl_1H1,2,4 Triazol-4-yl)phenyl)N-methyl-7,8-dihydro-5 H-0 butyl-[4,3-d]°-densidine-2,4-diamine (second dissolution) The enantiomer B) (45 9 mg, 〇〇99 mm〇1). LC_MS (Μ+Η)+=466.1 ο 'Η NMR (500 MHz, MeOD) δ ppm 8.00-8.06 (2 H,m), 7.25-7.35 (6 H,m),4.52-4.68 (2 H,m ), 4.1? (1 H, dd, J=1 1.29, 4.88 Hz), 3.96-4.02 (1 H, m), 3.92 (1 H't, J=4·88 Hz), 3.05 (3 H, s ), 2_38 (3 H, s). Not determined f Do not rely on the absolute stereochemistry of 5. Example Ί0 8-(4-Azyl)-N2-(3-methoxy-4·(4_methyl_ιη·Miso-1-yl)phenyl)^_substyl-7,8_ Dihydro _5^{-娘〇南和[4,3-(1] can bite-2,4-diamine

According to the actual Hungarian 2 (5 combination 2-gas-8-(4-phenylphenyl)_Ν_曱yl_7,8-dihydro_5Η_ 〇 bottom °Nand [4,3-d]pyrimidine _4_ amine (农7 美食# 尺0)(105.5 mg,0.340 mmol) and 3_decyloxy-4_(4-mercaptoimidazole-indolyl) aniline (69.1 mg, 0.340 mmol) and purified. 8-(4-Chlorophenyl)-N2-(3-methoxy_4_(4-fluorenyl-ex-imidazole-4-yl)phenyl)-indole 4-methyl-7 is obtained as a transparent colorless glass. 8-Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (120 mg, 0.203 mmol yield 59.7%). LC-MS (M+H)+= 477.2 A NMR (500 MHz, AfeOD) δ ppm 9·11 (1 H, s), 149653.doc -407· 201107311 7.76 (1 H, br. s.), 7.51-7.59 (2 H, m), 7.34 -7.46 (4 H, 7.26-7.33 (1 H,m), 4.52-4.75 (2 H,m), 4.17 (1, with •7=11.44,4.43 Hz), 4.08 (1 H,br. s. ), 3.88-4.04 (4, m) 3.17 (3 H, s), 2.44 (3 H, s). Example Ί0Α 8_(4_chlorophenyl)-N2-(3-methoxy-4-( 4-methyl-1H-imidazole-I.yl)m-yl)-N4-methyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2J-two @

\〇, NH

Separation of 8-(4-phenylphenyl)-indole 2-(3-methoxy- by multiple injections of palmitic SFC (AD-H 30x250 mm, 5 μΝί 20% MeOH (0.1% DEA)/C02) 4-(4-indolyl-1Η-imidazol-1-yl)phenyl)-indole 4-indolyl-7,8-diaza-5ί1 piperido[4,3-(1]pyrimidine-2,4- Diamine (solids / 70) to give 8-(4-phenylphenyl)-indole 2-(3-methoxy-4-(4-methyl-1Η-imidazole-1-) as an opaque coloured glass Phenyl)-phenyl 4-indolyl-7,8-dihydro-5-indole-[4,3-4] bite-2,4-diamine (first eluted, enantiomer Α LC-MS (Μ+Η)+=477·2. !H NMR (500 MHz, MeOD) δ ppm 7.84 (1 Η, d, 7=2.14 Hz), 7.62 (1 H, br. s.) , 7.30 (2 H, d, J=8.55 Hz), 7.19-7.28 (2 H, m), 7.06-7.15 (1 H, m), 6.94 (2 H, dd, /=8.55, 2.14 Hz), 4.48 -4.67 (2 H, m), 4.06-4.18 (1 H, m), 3.84-3.96 (2 H, m), 3.54 (3 H, s), 3.04 (3 H, s), 2_22 (3 H , s). The absolute stereochemistry of 7-14653.doc -408-201107311 was not determined. Example 70B 8-(4-chlorophenyl)-N2-(3-methoxy-4-(4-methyl) -1H-imidazole-diyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-di$

Separation of 8-(4-phenylphenyl^ C JJ-oxyl by multiple injections of palmitic SFC (AD-H 30x250 mm, 5 p τνί , 2 ί 20% MeOH (0.1% DEA)/C02) -4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4-indolyl-7,8-di-iso-pyrano[4,3-d]pyrimidine-2,4-di Amine (not 70), 8-(4-phenylphenyl)-N2-(3-decyloxy-4-(4-indolyl-lH-methane-1)-based opaque yellow glass Phenyl)-N4-mercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine (second elution, enantiomer B) . LC-MS (M+H)+= 477.2. 4 NMR (500 MHz, MeOD) δ ppm 7.85 (1 H,d, 7=2.14 Hz), 7.60-7.64 (1 H, m), 7.27-7.32 (2 H, m)5 7.19-7.24 (2 H, m), 7.06-7.11 (1 H, m), 6.90-6.96 (2 H, m), 4.48-4.64 (2 H, m), 4.06-4.14 (1 H, m), 3.84-3.92 (2 H, m), 3.51-3.57 (3 H, m), 3.01-3.06 (3 H, m), 2.19-2.25 (3 H, m). The absolute stereochemistry of f 705 was not determined. Example 71 8-(4-Chlorophenyl)-N2-(3-methoxy-4.(3-methyl-1H-1,2,4-triazole-149653.doc-409-201107311 1-based )phenyl)-N4-mercapto-7,8-dihydro-SH- mother sigma and [da] mouth. _2,4 diamine

According to the implementation of 26 combination 2-gas·8-(4-gas phenylmethyl-7J-diaza-5H-endo[4,3-d]pyrimidin-4-amine (agricultural / 钤6 (1〇5.5 mg, 0.340 mmol) and 3-methoxy-4-(3-methyl-1H-1,2,4-tris. sit-bu)aniline (Nongluo)) (69.5) Mg, 0.340 mmol) and purified to give 8-(4-phenylphenyl)-N2-(3-indoleoxy-4-(3-indolyl-1H-1,2,4-) as a clear, colorless glass. Triwax-1-yl)phenyl)-N4-mercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine. _ 2,4-Diamine TFA salt (120 mg, 0.203 mmol, yield 59.6%). 1^-MS (M+H)+=478.2. NMR (500 MHz, MeOZ) δ ppm 8.85 (1 H, s), 7.67 (1 H, d, /=8.55 Hz), 7.64 (1 H, s), 7.41-7.48 (2 H, m), 7.33 -7.40 (2 H, m), 7.18 (1 H, dd, J=8.55, 2.14

Hz), 4.52-4.73 (2 H, m), 4.17 (1 H, dd, "/=11.44, 4.42 Hz), 4.08 (1 H, br. s.), 3.94 (1 H, dd, 7=11.60 , 3.97 Hz), 3.91 (3 H, s), 3.17 (3 H, s), 2.45 (3 H, s). Example Ί1Α 8-(4-Phenylphenyl)-N2-(3-methoxy-4-(3-methylqH-i,2,4-triwax-l-yl)-yl)-~-基-7,8 - I, wind-51{- slightly verbose [4,3-(1]° 密-2,4-149653.doc -410- 201107311

Separation of 8-(4-chlorophenyl)-indole 2-(3-methoxyl by multiple injections of palmitic SFC (OD-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/CO 2 ) -4-(3-indolyl-1Η-1,2,4-triazol-1-yl)phenyl)_ν4-methyl-7,8-dihydro-5Η·pyrano[4,3-d The mouth bites -2,4-diamine (real eve / 7?), which gives 8-(4-indolyl)-Ν2-(3-indolyl-4-(3) in a separable brown glass -Methyl-1Η-1,2,4-dioxan-1-yl)benyl)-indole 4-methyl-7,8-dihydro-5Η-0 bottom 0-[4,3-d] Pyrimidine-2,4-diamine (first elution of 'enantiomer A) (24 mg, 0.050 mmol) 〇LC-MS (M+H)+=478.2 〇'H NMR (500 MHz, MeOD) δ ppm 8.57 (1 H, s), 7.93 (1 H, d, 7=2.14 Hz), 7.37 (1 H, d, J=8.85 Hz), 7.29-7.34 (2 H, m), 7.21-7.26 (2 H , m), 6.98 (1 H, dd, 7=8.70, 2.29 Hz), 4.50-4.66 (2 H, m), 4.13 (1 H, dd, 7=10.68, 3.97 Hz), 3.85-3.95 (2 H , m), 3.59 (3 H, s), 3.05 (3 H, s), 2.42 (3 H, s). The absolute stereochemistry of 7_M is not determined.

Example 71B 8-(4-Chlorophenyl)-indole 2-(3-,methyl-1Η-indole, 2,4-triazol-1-yl)phenyl)-indole 4-methyl-7,8-di Hydrogen·5Η-Nymphoteric[4,3-d] °Methoxy-2^4-diamine 149653.doc •411- 201107311

Separation of 8-(heart phenyl)-Ν2-(3-methoxy-4 by multiple injections of palmar SFC (OD-Η 30χ250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) -(3-indolyl-1Η-1,2,4-triazol-1-yl)phenyl)-indole 4-methyl-7,8-dihydro-5Η-β-deoxy[4,3-d ]mouth. -2,4-Diamine (5 #/ 7J), which gives 8-(4-chlorophenyl)-indole 2-(3-methoxy-4-(3-indole) in a separable brown glass Base-exit-1,2,4-triazole-buyl)phenyl)-:^4-mercapto-7,8-dihydro-5^piperazino[4,3-d]pyrimidine-2, 4-Diamine (Second Dissolution, Enantiomer oxime) (22 mg, 0.046 mmol) 〇LC-MS (M+H)+=478.2 NMR (500 MHz, MeOD) δ ppm 8.57 (1 H, s), 7.93 (1 H, ds /= 2.14 Hz), 7.36 (1 H, d, 7=8.55 Hz), 7.28-7.34 (2 H, m), 7.20-7.26 (2 H,m), 6.98 (1 H, dd, "7=8.55, 2.14 Hz), 4.50-4.66 (2 H, m), 4.13 (1 H, dd, 7 = 10.68, 3.97 Hz), 3.84-3.95 (2 H, m) , 3.59 (3 H, s), 3.04 (3 H, s), 2.41 (3 H, s). The absolute stereochemistry of 775 was not determined. Example Ί2 8-(4-Bromophenyl)-N2-(4-(4-a-1H-imidazo-yl)·, methoxyphenyl)·N4-methyl-7,8-dihydro- 5H 喵奂[4,3-d]pyrimidine_2&gt;4.diamine 149653.doc •412· 201107311

According to the purple combination 8-(4_bromophenyl)_2_chloro·N_methyl_7,8-dihydro_5H_pyrano[4,3-d]«* 密-4-amine #Ζί〇(95 mg, 0.268 mmol) and 4-(4-chloro-1H-imidazol-1-yl)_3_methoxyaniline (9 〇 mg, 0.402 mmol) and purified 8_(4_bromophenyl)_N2-(4-(4-chloro-1H-i-sodium-1-yl)_3·methoxyphenyl)_N4_methyl_7,8 as a brown solid _Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (38.5 mg, 0.059

M, yield 21.91%). LC-MS (M+H)+ = 541, 1. NMR (500 MHz, MeOD) δ ppm 7.83 (1 Η, br. s.), 7.70 (1 H, br. s.)5 7.17-7.42 (7 H, m), 6.96-7.06 (1 H, m) , 4.52-4.72 (2 H, m), 4.13-4.23 (1 H, m), 3.98 (1 H, br. s.), 3.87-3.96 (1 H, m), 3.62 (3 H, d, * 7=7.02 Hz), 3.06-3.16 (3 H,m). 8-(4-Bromophenyl)-N2-(3- gas-4-(5-methyl-1}{-1,2,4-trian-1-yl)phenyl)-'^4- Methyl-7,8-two wind-511-〇 bottom taste and [4,3-technical] mouth bite-2,4-diamine

According to the combination of 8-(4-bromophenyl)-2-methylmethyl-7,8-dihydro-5H-149653.doc-413-201107311 〇 喃 [4,3♦ 密密胺Rhenium D (95 mg, 0.268 mmol) and 3 defeated 4 (5-methyltrisal) aniline (spot mg, 0.402 mmol) and purified to give 8 (4 bromophenyl) n 2 (3_fluoro-4_ (5) -mercapto-1H-1,2,4-di"seat+yl)phenyl)_N4 fluorenyl-7,8 dihydro-_5H_ britant [4,3·(1] mouth bite-2,4- Diamine TFA salt (23 mg, 〇〇37 匪〇1, yield 13.75%). LC-MS (M+H)+=510.2. NMR (500 MHz,

MeOD) δ ppm 7.74 (2 Η, br. s.), 7.25-7.45 (7 H, m), 7.00- 7.12 (1 H, m), 4.53-4.73 (2 H, m), 4.17 (1 H, Dd, /=11.29, 4.88 Hz), 4.00-4.09 (1 H, m)5 3.89-3.99 (1 H, m), 3.71 (3 H, br. s·), 3_12 (3 H, s).

Examples 74A and 74B N-(4-(4-chloro-1H-imidazole-l-yl)-3-methoxyphenyl)-7 (4-fluorophenyl)-4-((S)_2.methylpyrrole Acridine-^yl)·5,% dihydrofuran[34_d]^ bite~2~amine

Individual diastereomers to (S)-2-chloro-7-(4-aminophenyl)-4-(2-indenyl) than slightly biting _1_yl)_5,7_di-argon °南和[3,4-d] 响β定(Preparation Me) (192.0 mg, 0.575 mmol), 4-(4-chloro-1H-imidazol-1-yl)_3_methoxyaniline (preparation A) (154 mg, 0.690 mmol), XANTPHOS (33.3 mg, 0.058 149653.doc • 414-201107311 mmol), Pd2 (dba) 3 (26.3 mg, 〇·029 mm〇1) and Cs2C〇3 (562 mg, Dioxane (2397 μί) was added to the mixture of 1.726 mmol). The mixture was flushed with nitrogen and placed in a capped vial and heated overnight at 10 °C. Cooled to room temperature and diluted with EtOAc. Filter through a celite® plug and spin to evaporate. The residue was taken on a silica gel and eluted with a gradient of EtOAc/Hex to afford a mixture as a mixture of diastereomers; _(4_(4_chloro-1H_-oxazol-1-yl)-3 - oxime Oxyphenyl)-7-(4-fluorophenyl)-4-(2-methylpyrrolidinyl-l-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine (189 mg, 0.363 mmol, yield 63.1%). The diastereomers were separated by chromatography on a palm of SFC (Chiralcel OJ column, 40% MeOH (.1% DEA) in C02) to afford Examples 74A and 74B. 74A: LC-MS (Μ+Η)+=521·2. 'H NMR (500 MHz, CDC13) δ ppm 7.60 (1 H, d, /=1.53 Hz), 7.50 (1 H, d, /=1.53 Hz), 7.35-7.41 (2 H, m), 7.00-7.10 (4 H, m), 6.93-6.99 (2 H, m), 5.82 (1 H, t, "7=2.44 Hz), 5.42-5.48 (1 H, m), 5.35-5.40 (1 H, m) , 5.29 (1 H, s), 3.72-3.79 (1 H, m), 3.68 (3 H, s)} 3.55-3.63 (1 H, m), 1.97-2.14 (3 H, m), 1.71-1.76 (1 H,m), I. 26 (3 H, d, /=6.41 Hz) 〇ExampleΊ5 N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl )-N4-ethyl-7-(4- phenyl)-5,7-dioxaf-[3,4-d] ° sessile-2,4-diamine 149653.doc 415 · 201107311

To 2-oxo-N-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-4-amine (preparative Mb) to dioxins Add 4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyaniline (5 mg 4) to a solution of (619 pL) and water (124 pL) (29.1 mg, 0.130 mmol) ), ginseng (dibenzylideneacetone) two (〇) (59.5 mg '0.065 mmol), 9,9-dimercapto-4,5-bis(diphenylphosphino)dibenzopyran (75 mg '0.130 mmol) and Na2CO3 (20.66 mg, 0.195 mmol). The resulting mixture was brought to 110 ° C in a sealed tube and stirred overnight. The reaction mixture was then diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Purification was carried out by flash chromatography (2D MeOH/CHCh) to remove the diphenyl bristo. The south ligand is such that it does not sink on the preparative column. The obtained oil was purified by preparative HPLC (C18, 50×250 mm, MeOH/H20/TFA) to afford N2-(4-(4-H-1H-imidazol-1-yl)- 3-indole as a transparent glass. Oxyphenyl)-N4-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine TFA salt (16.94 mg, 0.028 mmol, yield 21.91%). LC-MS (Μ+Η)+=481·0. NMR (500 MHz, CDC13) δ ppm 7.86 (1 Η,d,/=1.53 Ηζ), 7.56 (1 Η,d, "7=2.14 Ηζ), 7.43-7.49 (2 Η, m), 7.40 (1 Η , d, /=8.85 Hz), 7.37 (1 Η, d, J=1.22 Hz), 7.21 (1 H, dd, 7=8.55, 2.14 Hz), 7.17 (2 H, ts J=8.70 Hz), 6.10 (1 H, t, 7=3.20 Hz), 5.17 (1 H, dd, 7=11.44, 3.81 Hz), 5.04 149653.doc •416- 201107311 (1 H, dd, 7=11.60, 2.14 Hz), 3.86 (3 H, s), 3.66 (2 H, q, J=7.32 Hz), 1.32 (3 H, t, &gt; 7.32 Hz).

Example 75A #-(4-(4-Chloro-11{-imidazol-1-yl)-3-phenoxyphenyl)44-ethyl-7-(4-fluorophenyl)-5,7-dihydro吱 并[3,4_d] n close bite-2,4-diamine

Separation of Ν2-(4-(4-气-1Η-η米唑-1-) by multiple injections of palmitic SFC (OJ-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) Benzyl-3-phenyloxyphenyl)-N4-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine (Real 75), yielding a grayish-white clear foam-like NIOC4-gas-1H-imidazol-1-yl)_3_decyloxyphenyl)_n4-ethyl-indole-fluorophenyl)-5,7- Dihydropyrano[3,4-d]° bite 2,4-diamine (first enantiomer of 'enantiomer A) (20.7 mg '0.043 mmol, yield 10-71%). LC-MS (M+H)+=481.0. 4 NMR (500 MHz,MeOD) δ ppm 7.87 (1 Η, d, J=2.14 Hz), 7.68 (1 H, d, 7=1.22 Hz), 7.36- 7.42 (2 H, m), 7.22 (1 H, d, J=1.53 Hz), 7.13-7.17 (1 H, m), 7.04-7.11 (3 H, m), 5.79 (1 H, d, /= 2.14 Hz), 5.09-5.15 (1 H,m), 4.96-5.03 (1 H,m),3.71 (3 H,s),3.57 (2 H, q, •7=7.02 Hz),1.25-1.30 ( 3 H,m) 〇The absolute stereochemistry of the real day/75J was not determined. 149653.doc _41*7_ 201107311

Example 75B N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-(4-fluorophenyl)-5,7-dihydro. Shouted and [3,4-(1]° bite-2,4-diamine

Separation of Ν2-(4-(4-chloro-1Η-«米) by multiple injections of leather SFC (OJ-H 3〇x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C〇2) Sial-1-yl)-3-methoxyphenyl)-N4-ethyl-7-(4-oxophenyl)-5,7-dihydroefurano[3,4-d]pyrimidine- 2,4-Diamine, N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-n4-ethyl-7- 4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine (second elution of 'enantiomer B) (19.6 mg ' 0.041 mmol , yield 1 〇. 140/〇). LC-MS (M+H)+ = 481. NMR (500 MHz, MeOZ)) δ ppm 7.87 (1 Η, s), 7.68 (1 Η, s), 7.40 (2 Η, td, J=5.80, 2.44 Hz), 7.23 (1 H, s), 7.14 -7.18 (1 H, m), 7.06-7.12 (3 H, m), 5.80 (1 H, br. s.), 5.13 (1 H, dd, /=10.99, 3.05 Hz), 5.00 (1 H, d, ^=10.99 Hz), 3.72 (3 H, s), 3.57 (2 H, q, J=7.02 Hz), 1.25-1.31 (3 H, m). The absolute stereochemistry of the real day/7*55 was not determined. Example 7 6 N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3- Fluoropyridin-1-yl)·5}7-dihydrofuro[3,4-d]pyrimidin-2-amine 149653.doc -418- 201107311

According to: f 夕 / 26 combination 2-gas-7-(4_fluorophenylfluoro D than pyridyl _ i _ group)-5,7-dihydrofuro[3,4-d]pyrimidine (farm farm Mci) (49 mg, 〇145 mmol) and 4-(4-Gas-1H-imidazole-Im-yl)_3_methoxyaniline (32.4 mg, 0.145 mmol) N-(4-(4-chloro-indolyl)-1-yloxy-3-phenyloxy-7)-(4-phenylene)-4-((S) -3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine TFA salt (diastereomer 1 'racemate) (24.18 Mg, 0.038 mmol 'yield 26.1%). LC-MS (Μ+Η)+=525·1. 4 NMR (500 MHz, MeOD) δ ppm 7.92 (1H, d, J=1.53 Hz), 7.54 (1 H, br. s.), 7.47- 7.52 (2 H,m), 7.38-7.42 (2 H,m), 7.28 (1 H, dd, /=8.55, 2.14 Hz), 7.15-7.21 (2 H, m), 6.07-6.11 (1 H, m), 5.62 (1 H, dd, /=10.99, 3.97 Hz), 5.35-5.53 (2 H, m), 4.09-4.23 (2 H, m), 3.89-4.08 (2 H, m), 3.87 ( 3 H, s), 2.44 (1 H, br_ s·), 2.12-2.3 8 (1 H, m). Undetermined = the relative stereochemistry of your 76. Example 77 N-(4-(4-Chloro-indole-oxazol-1-yl)-3.methoxyphenyl)-7-(4-fluorophenyl)-4-((S)-3- Fluropyrrolidin-1-yl)-5,7-dihydrofuro p,4-d]pyrimidin-2-amine 149653.doc •419- 201107311

F

According to: T///26 combination 2-gas-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrole bite)-5,7-dihydrofuran [3,4 -d]pyrimidine (Amaranthus ^Mc2) (40 mg, 〇.118 mmol) and 4-(4-Gas-1H-imidazol-1-yl)-3-methoxyphenylamine (Preparation Α) (26 · 5 mg '0.118 mmol) and purified to give N-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxyphenyl)-7-(4-fluorobenzene) as a yellowish glass ()S(3-)-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-amine TFA salt (diastereomer 2, external elimination Spiral) (25.75 mg, 0.040 mmol, yield 34.0%). LC-MS (Μ+Η)+=525·1. NMR (500 MHz, MeOD) 5 ppm 7.88 (1 Η, d, J=\.22 Hz), 7.54 (1 H, s), 7.46-7.51 (2 H, m), 7.36-7.42 (2 H, m ), 7.16-7.25 (3 H, m), 6.08 (1 H,t,/=3.20 Hz), 5.52-5.60 (1 H,m), 5.36-5.52 (2 H,m),4.02-4.20 (2 H,m), 4.00 (2 H,s), 3.88-3.99 (1 H, m), 3.86 (3 H,s), 2.37-2.51 (1 H,m),2.14-2.37 (1 H, m) . The relative stereochemistry of the actual 77 was not determined. Example Anonymous N4-ethyl-N2-(3·fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl Dihydrofuran [,, 4~d] pyrimidine-2,4-diamine 149653.doc -420- 201107311

Combination of 2-gas-N-ethyl-7-(4-fluorophenyl)-5,7-difuroxo[3,4-d]pyrimidin-4-amine according to spur 75 _Fluor_4_(5_曱基2 4一坐1-基) This month's female (preparative C) (51.6 mg, 0.268 mmol) and pure, #, obtained N4-ethyl-N2 as a white solid -(3-fluoro-4-(5-fluorenyl-ml, 2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuran[3 , 4_d]pyrimidine _ 2,4-diamine TFA salt (64.1 mg, 0.114 mmol, yield 42.4. / 〇). 1^_ MS (M+H)+=450.0 〇*H NMR (500 MHz, MeOD) δ ppm 8.08 (1 H, s), 7.96-8.02 (1 H, m), 7.42-7.53 (4 H, m), 7.17 (2 H, t, /=8.85 Hz), 6.04 (1 H, t, 7=3.05 Hz), 5.18 (1 H, dd, J=ll.44, 3.51 Hz), 5.02-5.08 (1 H, m), 3.64 (2 H, q, J=7Λ2

Hz), 2.42 (3 H, s), 1.34 (3 H, t, /= 7.17 Hz).

#例78A ]^4-Ethyl-]^2-(3-fluoro-4-(5-royl-11{-1,2,4-triazol-1-yl)phenyl)-7-( 4-fluorophenyl)-5,7-dihydrofuropyrimidine _24.diamine

Separation of N4-ethyl·Ν2-(3 by multiple injections of palmar SFC (OJ-H 30x250 mm, 5 μΜ, 149653.doc •421 - 201107311 30% Me〇H (0.1% DEA)/C02) -fluoro-4-(5-fluorenyl-1Η-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuran[3 , 4-d]pyrimidine-2,4-diamine (real / / / 7 §), ν4_ethyl-Ν2-(3-fluoro-4_(5_methyl-1Η-1,2) as a white solid ,4-triazol-1-yl)phenyl)_7-(4-fluorophenyl)-5,7-dihydrocarbamate[3,4-d], biting 2,4-diamine (first dissolving) 'Enantiomer A' (25.8 mg, 0.057 mmol, yield 21.40%). LC-MS (M+H)+ = 450.0. H NMR (500 MHz, MeOD) δ ppm 8·15 (1 H, dd, “7=13.89, 2.29 Hz”, 8.03 (1 H, s), 7.39-7.47

(3 H, m), 7.33 (1 H, t, J=8.55 Hz), 7.07-7.12 (2 H, m), 5.84 (1 H, t, J=2.59 Hz), 5.14 (1 H, dd, 7=11.29, 3.36 Hz), 5.03 (1 H, dd, *7=11.14, 1.68 Hz), 3.53-3.61 (2 H, m), 2.39 (3 H, s), 1.27-1.32 (3 H,m ). Not measured: the absolute stereochemistry of /7. Example 78B 1^4-Ethyl-1^2-(3-fluoro-4-(5-methyl-1}{-1&gt;2,4-triazol-1-yl)phenyl)-7-( 4-Denphenyl)-5,7-dihydro cough and [3,4-d] mouth bite-2,4-diamine

Separation of Ν4-ethyl-Ν2-(3-fluoro-4-(5) by multiple extractions of SFC&gt; main shot (OJ-H 30x250 mm, 5 μΜ, 30% MeOH (0.1% DEA)/C02) -methyl-1Η-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-(!]pyrimidine -2,4-diamine (real: #/7§), which was obtained as a white solid. __ethyl-N2-(3-^-4-(5-fluorenyl-1Η-1,2,4 -三峻-1-yl) stupid)-7-(4- 149653.doc -422· 201107311 fluorophenyl)-5,7-dihydrofuro[3,4_cj]pyrimidine-2,4-diamine (Second dissolving, enantiomer B) (24.6 mg, 0.055 mmol, yield 20.40%). LC-MS (M+H)+=450.0. 4 NMR (500 MHz, CDC13) δ ppm 7.99 -8.06 (1 H, m)5 7.94 (1 H, s), 7.36-7.42 (2 H, m), 7.23-7.29 (1 H, m), 7.12 (1 H, dd, /=8.55, 1.83 Hz ), 7.02-7.08 (2 H, m), 5.86 (1 H, d, /=2.44 Hz), 5.01-5.21 (2 H, m), 3.50- 3.60 (2 H,m)' 2.40 (3 H, s), 1.27-1.33 (3 H, m). The absolute stereochemistry of 7S5 is not determined. Example Ί9Α N2-(4-(4-Ga-1H-imidazole-:yl)-, methoxyphenyl )_7_(4fluorophenyl)_N4-methyl-5,7-dihydrofuro[34_d]pyrimidine-2,4 diamine

According to your combination of 75-gas-7-(4-fluorophenyl)_N_methyl_5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (袅##Ma)(149 Mg, 〇533 〇1111〇1) and 4·(4-Gas-1H-imidazol-1-yl)_3·methoxyaniline (Preparation A) (119 mg, 0.533 mmol) and purified to give racemic N, (4(4_气_1H imidazolium)-yl-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuran[ 3,4-d]pyrimidine-2,4-diamine, by multiple injections of palmitic SFC (〇JH 3〇χ 250 mm ' 5 μΜ ' 35% MeOH (0_l./.DEA)/c〇2 ) to separate, to obtain a white powder to remove the foamy imidazolyl) _3_methoxyphenyl)-7-(4-fluorophenyl)·Ν4_methyl·5,7-dihydrofuran [3, 4_d]pyrimidine 149653.doc •423· 201107311 Acridine-2,4-diamine (first eluted, enantiomer α) (18·3 mg, 0.039 mmol, yield 7.36%). LC-MS (Μ+Η)+=467·0. 'H NMR (500 MHz, MeOD) δ ppm 7.89-7.94 (1 H,m), 7.65-7.69 (1 H,m), 7.36-7.42 (2 H, m), 7.20-7.24 (1 H, m) , 7.13-7.18 (1 H, m), 7.03-7.12 (3 H, m), 5.79 (1 H, br. s.), 5.08-5.16 (1 H, m), 4.95-5.03 (1 H, m ), 3.68-3.73 (3 H, m), 3.02-3.07 (3 H, m). The absolute stereochemistry of f not 75M was not determined. Example Ί9Β N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-di Hydrogen ° ° ° South and [3,4-0] pain ° -2,4-diamine

2-Chloro-7-(4-fluorophenyl)-N-mercapto-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (袅潆#Afa) according to the actual ^/75 combination (149 mg, 0.533 mmol) and 4-(4- gas-1H-imidazol-1-yl)-3-decyloxyaniline (preparation a) (119 mg, 0.533 mmol) N2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4- phenyl)-N4-indolyl-5,7-dihydrogen . Furano[3,4-d]pyrimidine-2,4-diamine, by multiple injections of palmitic SFC (OJ-H 30x250 mm, 5 μΜ, 35% MeOH (0.1% DEA)/C02) Separation gave N2-(4-(4-chloro-1H-11m. sit-1-yl)-3-methoxyphenyl)-7-(4-fluorocarbyl) as a yellowish-yellow foam -N4-methyl-5,7-dihydro-11f-[3,4·d]pyrimidine-2,4-diamine (second dissolving, enantiomer oxime) (22 1 mg , 149653.doc -424- 201107311 0.047 mmol, yield 8.89. /.). LC-MS (M+H)+=467. NMR (500 MHz, MeOD) δ ppm 7.92 (1H, d, /=2.14 Hz) 7.68 (1 H, d, /=1.53 Hz), 7.39 ( 2 Hs dd, /=8.70, 5.34 Hz), 7.22 (1 H, d, J=1.53 Hz), 7.15 (1 H, d, J=8.55 Hz), 7.〇4. 7.11 (3 H, m) , 5.79 (1 H, br. s.), 5.12 (1 H, dd, /=10.99 3.36 Hz), 4.99 (1 H,d,/=10.99 Hz), 3.70 (3 H,s), 3.05 (3

H, s). The absolute stereochemistry of the real Hungarian 795 has not been determined. Example 8Q N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)- 7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-

The preparation A (〇.1〇2 g, 0.560 mmol), preparation Ma (0.160 g, 0.560 mmol), Na2CO3 (0.119 g, 0.110 mmol) and xantphos (0,325 g, 0.560) were purged with argon at room temperature. Methyl) solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.310 g, 0.21 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 1 ° C &gt; c for 24 hours. The reaction mass was filtered through a pad of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (75 mL x 2). The mixture was washed with a brine solution (5 〇 mL) and 149653.doc • 425-201107311. The layer was dried over anhydrous Na 2 S 〇 4 and evaporated under reduced pressure to give a crude compound. 120 mesh), use 21. /. The petroleum ether solution of ethyl acetate was used as a mobile phase to purify the crude compound to give bis-(4·(4-Gas-1H4 s s)) 3-methoxyphenyl)·4_(3,3_ Difluoroazetidinyl) (7-(4-phenylene)_5,7-dihydroindolo[3,4_d]indole-2-amine (〇.9〇g, 4〇0/ 〇). LC MS (Μ+Η)+=529 2. 4 Guansi 400 MHz, DMs〇__: s ppm 9 6 (1H, s), 7 99 (1Η,

s)5 7.98 (1H, s), 7.76-7.41 (3H, m), 7.23-7.13 (4H, m), 5.87 s)5 5.33 ( 1H, dd, J=ll.l, 3.2 Hz), 5.17 ( 1H, dd, slice ll, 3.2), 4.67 (4H, m), 3.72 (3H, s). Enantiomeric examples 80A and 80B were obtained by separation of the racemic mixture by palm chromatography, both having the same spectral data. Example 81 N2-(4-(4-Gas-1H4 succinyl)·3-methoxyphenyl)- Ν4_((κ)small propylethyl)-7-(4-fluorophenyl)_5, 7•Dihydrofuro[3,4_d]pyrimidine-24•II

Saddle TFA salt

2-2-N-((R)-1-cyclopropylethyl)_7_(cardiacfluorophenyl)_5,7-diaza is bitten and [3'4♦ bite·4_amine (preparation) Mf) and 4-(4-Gas-1H-isazole small group) _ diastereomer mixture 149653.doc -426- 201107311 % decyloxyaniline (preparation A) reacts as described in example 112 , N2-(4-(4-Ga-1H-imidazol-1-yl)-3-indolyloxyphenyl)-N4-((R)- is obtained as a mixture of two diastereomers. 1-cyclopropylethyl)-7-(4. fluorophenyl)·5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine TFA salt (Example 81). LC-MS (M+H)+ = 521_3.丨H NMR (5〇〇 MHz, MeOD) δ ppm 7.82 (d, J=1.53 Hz, 1 H) 7.44-7.51 (m, 3 H) 7.38 (d, J=8.55

Hz,1 H) 7.35 (d,J=1.53 Hz,1 H) 7.14-7.22 (m,3 H) 6.08

(br· s., 1 H) 5.21 (dd, J=11.60, 3.05 Hz, 1 H) 5.07 (dd, J-11.44, 2.59 Hz, 1 H) 3.84 (s, 3 H) 3.30(m, 1 H ) 1.38 (d, J-6.41 Hz, 3 H) 1.06-1.13 (m, 1 H) 0.59-0.66 (m, 1 H) 0.54 (d, J-3.97 Hz, 1 H) 0.37 (d, J=4.88) Hz, 1 H) 0.28 (d, J = 4.88 Hz, 1 H). Example 82

N2-(3-Fluoro-4-(5-methyl-1H_12 4 -triazole-Iyl)phenyl)-7-(4-fluorophenyl)-indole 4-methyl-5,7-dihydrofuran[3&gt ;4_d]pyrimidine_2&gt;4_diamine TFA salt

2-Ga-7-(4-fluorophenyl)_N_indolyl-5,7-dioxafuro[3,4-d]pyrimidin-4-amine (preparation *Ma) and 3-fluoro_4_(5 _ fluorenyl jh-ha triazole _ fluorenyl) aniline (preparation C) reacts as described in Example 112 to give N2_(3_'_ 4-(5-methyl-1H-1,2,4-three Zin-1-yl)phenyl)_7_(heart fluorophenyl)_Ν4·methyl_5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine TFA salt (Example 82) . 149653.doc -427- 201107311 LC-MS (M+H) =436.1. 4 NMR (500 MHz, MeOD) δ ppm 8.16 (dd, J=13.89, 2.29 Hz, 1 H) 8.03 (s, 1 H) 7.38 -7.47 (m, 3 H) 7.34 (t, J=8.70 Hz, 1 H) 7.05-7.14 (m, 2 H) 5.85 (d, J=1.83 Hz, 1 H) 5.16 (br. s., 1 H 5.04 (br. s., 1 H) 3.07 (s, 3 H) 2.39 (s, 3 H) ° The racemic mixture is isolated by palm chromatography to give the enantiomer in the form of the free amine. Both body examples 82A and 82B' have the same spectral data. Example 83 N-(4-(4-Gas-1Η-imidazole-4-yl)-hydroxymethoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidine "-based" ·%% dihydrofuro[34_d]pyrimidine-2-amine

Two TFA Salt CI

a mixture of diastereomers such that 2chloro-7-(4-fluorophenyl)_4_(())_3_fluoroindole + ketone dihydroceps and [3,4-d]pyrimidine (preparation岣) and 4 ♦ gas-ih_imidazole small group with methoxyaniline (preparation of the article as described in Example 112 to give a base in the form of a mixture of two diastereomers)-3- Methoxyphenyl)_7·(4 rhyme)_4_((R)m each bite small base)_ 5,7·dihydrogen and [3,4_-dean-2-amine di-TFA salt (Example 83) 〇LC side 149653.doc 201107311 (M+H^SSS.hiHNMRpOOMI^MeODWppmT.SSCbr·s.,1 Η) 7.57 (br. s·,1 Η) 7.43-7.52 (m,2 Η) 7.32-7.41 (m , 2 H) 7.22-7.29 (m, 1 H) 7.10-7.22 (m, 2 H) 6.00-6.11 (m, 1 H) 5.38-5.50 (m, 3 H) 4.10 (br. s., 2 H) 3.90 (br. s., 2 H) 2.3 1-2.5 1 (m, 2 H). Separation of the mixture of the two diastereomers by palm chromatography gave the two diastereomeric examples 83 and 83B as the free amine. Example 83A: LC-MS (M+H)+=525.2. 4 NMR (500 MHz,

MeOD) δ ppm 7.80 (d, J=1.83 Hz, 1 H) 7.69 (d, J=1.53 Hz, 1 H) 7.43 (dd, J=8.70s 5.34 Hz, 2 H) 7.23 (d, J=1.22 Hz , 1 H) 7.04-7.20 (m, 4 H) 5.77 (br. s., 1 H) 5.50-5.59 (m, 1 H) 5.27-5.39 (m5 2 H) 4.00 (d, J=11.90 Hz, 1 H) 3.82-3.96 (m, 2 H) 3.63-3.82 (m, 4 H) 2.26-2.42 (m, 2 H). Example 83B: LC-MS (M+H)+ = 525.2. NMR (500 MHz,

MeOD) δ ppm 7.81 (d, J=1.83 Hz, 1 H) 7.69 (d, J=1.53 Hz, 1 H) 7.39-7.47 (m, 2 H) 7.24 (d, J=1.53 Hz, 1 H) 7.16 -7.21 (m, 1 H) 7.05-7.16 (m, 3 H) 5.80 (t, J=2.59 Hz, 1 H) 5.51 (dd, J=10.38, 3.05 Hz, 1 H) 5.36-5.46 (m, 2 H) 3.91 (m, 2 H) 3.66-3.86 (m, 5 H) 2.23-2.42 (m, 2 H). Example 84 N-(4-(4-Chloro-1Η-imidazole-i-yl)_3·methoxyphenyl)-4_((286Κ)_ 2'6-dimethyl(indolyl-morpholinyl)) _7·(4_fluorophenyl)_5,7 dihydrofuro[34_d]pyrimidin-2-amine diTFA salt 149653.doc •429· 201107311

St chlorine, 4 ships called 2,6·: methyl (Ν·Merlinky)) 1 (44 phenyl)-'- 虱 喃 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ (4_Chloro_ιη miso_) methoxyaniline (preparation Α) The reaction piece was generated as described in Example 112 to Ν-(4·(4·气-1Η-isazo-1·yl)-3 -Methoxyphenyl)-4-((2S,6R)-2,6-diindenyl (Ν-Merlenyl)) 7_(4Fluorophenyl 5,7-dichloro-butane [3, 4-d]pyrimidin-2-amine di-TFA salt (Example 84). LC_MS (Μ+Η)+= 551.2 〇'H NMR (400 MHz, MeOD) δ ppm 7.80 (d5 J=1.51 Hz, 1 H) 7.55 (d5 1=2.27 Hz, 1 H) 7.35-7.46 (m, 2 H) 7.23-7-33 (m, 2 H) 7.01-7.18 (m,3 H) 5.91 (t, J=2.77 Hz, 1 H 5.42 (dd, J=10.45, 3.40 Hz, 1 H) 5.28 (dd, J=l〇.32, 2.27

Hz, 1 H) 4.16 (br. s., 2 H) 3.60-3.78 (m, 5 H) 2.81 (ddd, J=13.41, 10.51, 3.53 Hz, 2 H) 1.21 (d, J = 6.04 Hz, 6 H). Separation of the racemic mixture by palm chromatography afforded the enantiomers in the form of the free amines. Examples 84A and 84B. LC-MS (M+H)+ = 551.2. ]H NMR (500 MHz, MeOD) δ ppm 7.77 (d, J=2.14 Hz, 1 H) 7.69 (d, J=1.53 Hz, 1 H) 7.35-7.50 (m, 2 H) 7.24 (d, J= 1.53

Hz, 1 H) 7.18 (d, J=8.55 Hz, 1 H) 7.10 (t, J=8.70 Hz, 2 H) 7.05 (dd, J=8.55, 2.14 Hz, 1 H) 5.80 (d, J=2.44 Hz, 1 H) 5.42 (dd, J=10.38, 3.05 Hz, 1 H) 5.28 (dd, J=10.38, 1.83 149653.doc • 430· 201107311

Hz, 1 Η) 4.16 (br. s., 2 Η) 3.61-3.76 (m, 5 Η) 2.60-2.80 (m, 2 H) 1.23 (d, J = 6.41 Hz, 6 H). Example 85 _(4-(4-Chloro-1H-imidazo-i-yl)_3_methoxyphenyl yN4_methyl-8-phenyl-6,8-dihydro-51{-pyran [3,4-(1]pyrimidine-2,4-diamine

The preparation Α(〇· 168 g, 0.75 mmol), preparation Na (0.23 g, 0.834 mmol), Na 2 CO 3 (0.176 g, 1.6 mmol) and xantphos (0.482 g, 0.834 mmol) were purged with argon at room temperature. The solution in the second &quot; cacao/water (9:1) for 1 hour. Pd(dba)3 (0.38 g, 〇_417 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. Here. The reaction mass was heated under the arm for 24 hours. The reaction was filtered through a pad of celite and washed with ethyl acetate. The liquid was evaporated under reduced &amp; and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (75 mL x 2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na? Purification of the crude compound by preparative HPLC (EtOAc EtOAc (EtOAc (EtOAc)) Phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine (0.140 g, 36.2%). LC-MS (M+H)+ = 463.2. !H NMR (400 MHz, DMSO-c/(5): δ ppm 9.06 (1H, s), 7.96 (1H, s), 7.72 (1H, s), 7.4 (1H, s), 7.36-7.30 (5H ,m),7.13 149653.doc •431 - 201107311 (2H, m), 6.94 (1H, m), 5.43 (1H, s), 3.95 (1H, m), 3.81 (1H, s), 3.53 (3H, s), 2.97 (3H, d, ./=4.4 Hz), 2.52 (1H, m), 2.45 (1H, m). Example S6 N2-(3-fluoro-4-(3-methyl_ih-1) , 2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2, 4-diamine

The preparation Β(〇·ιΐ9 g, 0-62 mmol), preparation Na (0.19 g, 0.68 mmol), Na2CO3 (0.146 g, 1.37 mmol) and xantphos (0.399 g, 0.689 mmol) were purged with argon at room temperature. The solution in dioxane / water (9:1) was taken for 1 hour. Pd(dba)3 (0.315 g, 344·344 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. In u 〇. The reaction mass was heated under the arm for 24 hours. The reaction mass was filtered through a pad of Celite (EtOAc) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (75 mL x 2). The combined organic layers were washed with brine brine, dried over anhydrous NajEtOAc, and evaporated Purification of the crude compound by preparative HPLC (acetonitrile containing EtOAc / EtOAc / EtOAc / EtOAc) EtOAc (m.)基)phenyl)_N4_methyl_8_phenyl·6,8 dihydro-5H-piperazolo[3,4-d]pyrimidine-2,4-diamine (0.120 g, 30%). LC-MS (M+H)+= 149653.doc -432-201107311 432.2.丨H NMR (400 MHz, DMSO-c/6): δ ppm 9.33 (1H, s), 8.68 (1H, s), 8.03 (1H, m), 7.42-7.24 (7H, m), 6.98 (1H, ^s), 5.44 (1H, s), 4.06 (1H, m), 3.84 (1H, m), 2.95 (3H, d, */=4.4 Hz), 2.59 (1H, m), 2.44 (1H, m ), 2.34 (3H, s). Example 87 N2-(Hongfu·4·(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl-6,8-di Hydrogen-5}{-pyrano[3&gt;4- phenanthroline-2,4-diamine

Prepare C (〇. 119 g, 0.62 mmol), preparation Na (0.19 g, 0.68 mmol), Na2CO3 (0.146 g, 1.37 mmol) and xantphos (0.399 g' 0.689 mmol) with argon at room temperature. The solution in 2 ° of smoldering/water (9:1) was used for 1 hour. Pd(dba)3 (0.315 g, 0.344 mmol) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 11 ° C for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (75 mL×2), and the combined organic layer was washed with brine (5 mL), dried over anhydrous Na? The crude compound was purified by preparative EtOAc (EtOAc (EtOAc) elute Base)·Ν4_methyl_8_phenyl·6,8-dihydro-5h_pyrano[3,4-d]pyrimidine-2,4-diamine (0.130 g, 44%). LC-MS (M+H)+= 149653.doc -433 · 201107311 432.2. 4 NMR (400 MHz, DMSO-M): δ ppm 9.38 (1H, s), 8.04 (1H, s), 8.01 (1H, s)5 7.44 (1H, m)5 7.34-7.27 (6H, m), 6.99 (1H, bs), 5.43 (1H, s), 4.06 (1H, m), 3.83 (1H, m), 2.95 (3H , d, J=4.4.0 Hz), 2.51 (1H, m)5 2.44 (1H, m), 2.27 (3H, s). Example 88-(4-(4-Chloro-11{-imidazol-1-yl)-3-methoxyphenyl)-]-ethyl-8-(4-fluorophenyl)-6,8- Dihydro-51{-pyrano[3&gt;4-(1]pyrimidine-2,4-diamine

Prepare A (0.09 g, 0.38 mmol), preparation Oa (0.15 g, 0.48 mmol), Na2CO3 (0.103 g, 0.97 mmol) and xantphos (0-282 g, 0.41 mmol) in argon at room temperature The solution in the smoldering/water (9:1) for 1 hour. Pd(dba)3 (0.270 g, 0.24 mmol) was added to the reaction mixture and the resulting solution was again purged for one hour. The reaction mass was heated at i 1 (rc) for 24 h. The reaction was filtered over EtOAc (EtOAc) eluting with EtOAc EtOAc. The aqueous solution was extracted, and the combined organic layer was washed with brine (5 mL), dried over anhydrous Naj.sub.4, and evaporated under reduced pressure to give a crude compound, which was obtained by column chromatography (6 〇·12 〇). 35% ethyl acetate in petroleum ether was used as the mobile phase to purify the crude compound to give N2-(4-(4-H-1H-imidazol-1-yl)-3-methyl as an off-white solid 149653.doc 201107311 Oxyphenyl)-N4-ethyl_8_(4-phenylene)-6,8-dihydro-5?1-° benzo[3,4-(!] mouth bite-2,4- Diamine (〇.9〇g '55%). LC-MS (M+H)+=495.2. NMR (400 MHz, DMSO-m): δ ppm 9.06 (1H, s), 7.88 (1H, s) , 7.73 (1H, m), 7.42 (1H, m), 7.33-7.44 (2H, m), 7.14-7.15 (4H, m), 6.92 (1H, m), 5.44 (1H, s), 3.96 (1H , m), 3.82 (1HS m), 3.57 (3H, s), 3.50 (2H, m), 2.45 (2H, m), 1.21 (3H, m). Separation of racemization by palm chromatography Mixture, get the opposite Construct examples 88A and 88B, both have the same spectral data. Example 89 N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl- Ο-Ο-fluorophenyl)-N4-methyl-6,8-dihydro-5H-pyry and [3,4-d] ° close bite-2,4-

F Purified preparation A (0-029 g, 0.10 mm )l), preparation 〇b (〇.050 g, 〇·ΐ 4 mmol), Na2C03 (〇.030 g, 0.28 mmol) and argon at room temperature Xantph〇s (0.080 g, 0.14 mmol) was used in two. The solution in the smoldering / water (9:1) for 1 hour. Pd(dba)3 (〇 〇 78 g, 〇 〇 7 mm 〇 1) was added to the reaction mixture and the resulting solution was again purged for a few hours. In u 〇. The reaction mass was heated under the arm for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with acetic acid 149653.doc -435 - 201107311. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with diethyl succinyl ester (75 mL x 2). The combined organic layers were washed with brine (5 mL) and dried over anhydrous NaHEtOAc. The crude compound was purified by column chromatography (60-120 mesh) using 35% ethyl acetate-brown oil as a mobile phase to give a white solid (2) (4-(4- gas-1H-imidazole). -1-yl)-3-decyloxyphenyl)_N4_ethyl_8-(4-fluorophenyl)-N4-fluorenyl-6,8-dihydro-5H-pyrano[3,4_d] Pyrimidine_2,4_

Diamine (0.020 g, 30%). LC-MS (M+H)+ = 509.2. NMR (400 MHz, OUSO-d6): δ ppm 9.12 (1Η, s), 7.75-7.81 (2H, m), 7.38-7.44 (3H, m), 7.15-7.24 (4H, m), 5.51 (ih, s), 4.03 (1H, m), 3.49-3.67 (5H, m), 3.09 (3H, m), 3.01-3.06 (1H, m), 2.51-2.59 (2H, m), 1.22 (3H, t, "7=7.2 Hz).

Example 90 A N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3 - Fluorine σ ratio 嘻a -1-yl) _6,8-diaza-5H-pyrano[3,4-d] ° octagonal 2-amine

F The preparation Α (0·063 g, 0.20 mm〇1), the preparation Ocl (0.110 g, 〇·3 mmol), Na2C〇3 (〇.〇66 g, 〇6) were purged with argon at room temperature. Mm〇i) and xantphos (0.181 g, 0·3 mmol) in a solution of di-burn/water (9:1) 149653.doc -436- 201107311

1 hour. Pd(dba)3 (0172 g, 0.10 mm〇i) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 11 Torr for 24 hours. The reaction mass was filtered through a pad of Celite (EtOAc) eluting with ethyl acetate. The aqueous solution was extracted with ethyl acetate (75 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Naj. The crude compound was purified by column chromatography (60-120 mesh) using 35% ethyl acetate EtOAc solution as mobile phase to afford ice (4-(4-H-1H-imidazole-1-) 3-)-3-methoxyphenyl)_8_(4-fluorophenyl)-4-((R)-3-fluoropyrrolidinyl)-6,8-dihydro-5H-pyrano[3, 4 d]pyrimidine-2-amine (0.050 g, 60%). LC-MS (Μ+Η)+=539·0. iH nmr (400 MHz, DMSO-af &lt; 5): δ ppm 9.12 (1H, s), 7.75 (2H m) 7.39-7.44 (3H, m), 7.15-7.22 (4H, m), 5.50 (lH, s ), 5 38 (1H, m), 3.82-4.09 (6H, m), 3.68 (3H, s), 2.98 (2H, m) 2.50-2.43 (2H, m). Example N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-oxa 4-((R)-3-fluoropyrrolidinyl)- 6,8-Dihydro-5H-pyrano[3,4_幻。密唆

149653.doc -437 - 201107311 The preparation Α(〇·〇63 g,〇2〇mmoi), preparation 〇c2 (〇.110 g, 0.3 mmol), Na2C03 (〇. 〇66 g, 0.6 mmol) and xantphos (0.181 g, 〇.3 mmol) in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0172 g, 0.10 mmol) was added to the reaction mixture and the resulting solution was again purged for one hour. The reaction mass was heated at 11 (rc) for 24 hours. The reaction mixture was filtered over celite (EtOAc) eluting with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with aq. EtOAc (3 mL), EtOAc (EtOAc)EtOAc. The crude petroleum compound was purified as a mobile phase to give N-(4-(4-chloro-1H-imidazol-1-yl)_3·decyloxyphenyl)_8_(4) as a white solid. Fluorophenyl)· 4-((R)-3-fluoropyrrolidine-fluorenyl-yl)-dihydro-5H-pyrano[3,4d]pyrimidine-2-amine (0.070 g, 63%). LC -MS (M+H)+=539.0 » 4 NMr (400 MHz, DMSO-state: δ ppm 9.16 (1H, s), 7.81 (1H s) 7·74 (1H, s), 7.73 (1H, s) ,7 42 (2H,m),717 7 li 5- 54 (1H, s)3 5.43 (1H, m), 4.12-3.57 (6H, m), 3.34 (3Hj 2.97 (2H,m), 2.50-2.43 (2H,m). ' '

Example 91A N-(4-(4-Ga-1H-imidazolyl y3_foxyphenyl)_8_(4-fluorophenyl) 4-((S)-3-fluoropyrrolidine-:^yl)^2 Hydrogen-5H_piperidinium 2-m 149653.doc -438- 201107311

The preparation Α(〇·〇63 g, 0.20 mmol), the preparation Odl (〇.ll〇g, 0.3 mmol), Na2C〇3 (〇〇66 g, 〇6 mm〇) were purged with argon at room temperature. l) A solution of φ and xantphos (0.181 g, 〇·3 mmol) in dioxane/water (9:1) for 1 hour. Pd(dba)3 (0172 g, 〇.1〇 mm〇i) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated under 1 i 24 for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (75 mL x 2). The combined organic layers were washed with a brine solution (5 mL), dried over anhydrous NazSO4, and evaporated. 35 was used by column chromatography (60-120 mesh). /. The crude compound was purified as a mobile phase to give N-(4-(4-y-1H-imidazol-1-yl)-3-methoxyphenyl)-8 as an off-white solid. ·(4.Fluorophenyl)_ 4-((S)_3-fluoropyrrolidinyl)-6,8-dihydro-5-pyrano[3,4-pyrimidine_

2-amine (0.040 g, 40%). LC-MS (Μ+Η)+=539·〇. iH NMR (400 MHz, DMSO-state: δ ppm 9.25 (1H, s), 7.77 (1H s) 7.77 (1H, s), 7.45 (3H, m), 7.21 (4H, m), 5.53 (lH} s ), 5.43 (1H, m), 4.12-3.57 (5H, m), 3.34 (3H, s), 3.33 (lH, m), 3.20 (1H, m), 2.73 (1H, m), 2.31-2.06 ( 2H, m).

Example 91B 149653.doc -439· 201107311 N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-( (S)-3-fluoro.pyrrolidin-yl-yl)^;-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine

F Purified preparation A (0. 〇 63 g, 0.20 mmol), preparation Od2 (0.1 l g, 0.3 mmol), Na 2 CO 3 (0.066 g, 0.6 mmol) and xantphos (0.181 g) with argon at room temperature. , 0.3 mmol) of the solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0172 g, 0.10 mm〇l) was added to the reaction mixture and the resulting solution was again purged for 1 hour. The reaction mass was heated at 11 (TC) for 24 hours. The reaction mixture was filtered over celite (EtOAc) eluting with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted. The combined organic layer was washed with brine (5 mL) and dried over anhydrous Na.sub.2SO.sub. The ethyl acetate-purified solution was used as the mobile phase to purify the crude compound to give N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl) as an off-white solid. 8-(4-Fluorophenyl)-4_((S)-3-fluoropyrrolidinyl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2- Amine (0.039 g, 39%). LC-MS (M+H)+ = 539.0. NMR (400 MHz, OUSO~d6): δ ppm 9.15 (1 Η, s), 7.81 (1H, s), 7.74 (1H , s), 7.43 (1H, s), 7_37 (2H, m), 7.19 (4H, m), 5.54 (1H, 149653.doc • 440-201107311 s), 5.43 (1H, m), 4.13-3.69 ( 6H, m), 3.33 (3H, s), 2.96 (2H, m), 2.24-1.91 (2H, m). Example 92^2-(4-(4-chloro-11{-imidazol-1-yl) -3-methoxyphenyl)_7_(4_chlorophenyl)· 1 ^4,!^4-dimethyl-6&gt;7-dihydro-51^-cyclopenta[(^] bite-2,4-diamine.

2-Ga-7-(4-Phenylphenyl)-7V, iV-dimethyl-6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine (98 mg' 0.318 Methyl) to 4-(4-Ga-1//-imidazol-1-yl)-3-decyloxyaniline (71.1 mg, 0.318 mmol) in acetic acid (1 · 〇〇〇mL) and THF (1 mL In the solution. The reaction mixture was heated at 75 ° C overnight. Partial conversion to the desired product was observed. The reaction was further heated under 12 Torr for 6 hours. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate dissolving fraction 'to give A^-(4-(4-gas-1//-imidazol-1-yl)-3-yloxyphenyl)-7-(4-chlorophenyl)-#,#- Dimercapto-6,7-dihydro-5//-cycloindolo[d]pyrimidine-2,4-diamine TFA salt (17.2 mg '0.028 mmol, yield 8.70%). LC-MS (Μ+Η)+=495·1. NMR (500 MHz, CDC13) δ ppm 11.80 (1Η, s)5 7.61-7.72 (1H, m), 7.34-7.42 (2H, m), 7.27-7.33 (2H, m), 7.21 (2H, d, y =8.5 Hz), 7.16 (1H, d, 7=9.2 Hz), 7.06 (1H, d, /=1.5 Hz), 4.30-4.41 (1H, m), 3.82 (6H, s), 3.48 (1H, br s.), 3.31-3.39 (2H, m), 3.18-3.27 (1H, m), 2.58-2.80 (2H, m), 2.14-2.29 (1H, m). 149653.doc -441 - 201107311 Example 93 Dihydro-5 ugly-cyclopenta[d]pyrimidine (4 (4-chloro-1&quot;_imidazolyl)·3_methoxyphenyl)_7_(4 gas base )

4_(3,3-difluoroazetidin-1-yl)-6,7-di 2-oxa-7_(4·gasphenyl)_4_(3,3-difluoroazetidine Indyl dihydro- 5//-cyclopenta[d]pyrimidine (70 mg, 〇.i97 mmol) was added to 4·(4_chloroindol-1-yl)-3-decyloxyaniline (52.7 mg, 0.236 mm 〇l) in a solution of acetic acid (1 mL) and THF (1.000 mL). The reaction mixture was heated under microwave for 6 hours at 120 ° C. The crude reaction mixture was purified by preparative HPLC. Obtaining JV_(4_(4_chloro-li/-imidazolyl-1-yl)-3-methoxyoxyphenyl)-7-(4-chlorophenyl)-4-(3,3-dicyclobutane -1-yl)-6,7-dihydro-5/ί-cyclopenta[d]pyrimidin-2-amine TFA salt (8.7 mg, 0.013 mmol, yield 6.46%). LC-MS (M+H ) == 543.1. NMR (500 MHz, CDC13) δ ppm 1 1.85-11.99 (1H, m), 7.93 (1H, s), 7.38-7.45 (1H, m), 7.31 (2H, d, J=8.2 Hz ), 7.19 (3H, t, J=8.2 Hz), 7.10 (1H, d, J=1.5 Hz), 4.37-4.47 (1H, m), 3.85 (3H, s), 3.45-3.51 (1H, m) , 3.07-3.18 (2H, m), 2.94-3.04 (2H, m), 2.67-2.81 (2H, m), 2.19-2.37 (2H, m). Example 94 149653.doc -442- 201107311 #2-( 4-(4-gas-li/-mi saliva" ― 卜 曱 曱 曱 苯基 ) ) ) ) ) -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6 -6

Add 2-gas-7-(4-oxaphenylcarbazyl-6,7-dihydro-5/ί-cyclopenta[d]pyrimidine-4-amine (101 mg' 0 343 mm〇1) To 4_(4_气_17/·imidazole-b

Benzyl-3-methoxyaniline (77 mg, 0.343 mmol) in EtOAc (2 mL) and THF (2 mL). The reaction mixture was heated at 8 ° C overnight. Partial conversion to the desired product was observed. Again at 120. (The reaction was heated for 6 hours. The crude reaction mixture was purified by preparative HPLC, and the appropriate fractions were evaporated to give W-(4-(4- gas-1 </RTI> </RTI> <RTI ID=0.0> )_7_(4_chlorophenyl)-//mercapto-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine TFA

Salt (35.5 mg '0.059 mmol, yield 17.19%). LC-MS (M+H)+=481.3 °]H NMR (500 MHz, CDC13) δ ppm 11.08 (1 Η, s), 8.33 (1H, S), 7.48 (2H, d, 7=2.1 Hz), 7.30 (2H, d, */-8.2 Hz), 7.20 (in, d, J=1.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H , m), 3.97 (1H, s), 3.86 (3H, s), 3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, "7=8.7, 5.3 Hz), 2.20-2.32 (1H, m).

Examples 94A and 94B (S)-N2-(4-(4-Gas-1H-imidazole a-yl)·3_methoxyphenyl)-7-(4-chlorophenyl)-indole-methyl-6, 7-Dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine 149653.doc •443· 201107311 λ (R)-N2-(4-(4-chloro-1 Η-imidazole-1- 3-methoxyphenyl)-7-(4-chlorophenyl)-indole 4-methyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine

Purification of iV2-(4-(4-gas-Ι/f-imidazol-1-yl)-3-methoxyphenyl)-7-(4-phenylphenyl fluorenyl-6,7 using palmitic SFC -Dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine racemic mixture (37 mg, 0.077 mmol, as expected) gave 10.5 mg peak A (not 9 M) And 13.6 mg peak B (real you 945). SFC method: Chiralpak 〇JH (4.6x250 mm, 5 μΜ), 35% sterol (0.1% diethylamine) in C〇2, 35 ° C, flow rate 2.0 mL/min, maintain 20 min '268 nm absorbance, inject 5 pL 2 mg/mL in 50:50 sterol/gas imitation solution (multiple stack injections), (peak A) = 5.3 min, iR (peak B) ) = 14.9 minutes "The absolute stereochemistry of individual enantiomers is not determined. The LC-MS and 1H NMR analysis of the separated enantiomers and the racemates Not the same as 94. Example 9 5 N2-(4-(4-Chloro-1indole-5-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl) 44 ,:--Dimethyl-6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-diamine 149653.doc -444- 201107311 ,〇

2-Chloro-7-(3,4-difluorophenyl)dimethyl-6,7-dihydro-5//-cyclopenta[d]»-biti-4-amine (178 mg, 0.575 Methyl) was added to 4-(4- gas-1/ί-flavor.sodium-1-yl)-3-methoxyanilide (141 mg, 0.632 mmol) in acetic acid (2 mL) and THF (2.000 mL) In the solution. The reaction mixture was heated at 80 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #2-(4-(4-gas-1&quot;-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-# , 7\^-dimercapto-6,7-dihydro-5//-cyclopenta[(1]pyrimidine-2,4-diamine TFA salt (144.1 mg, 0.233 mmo yield 40.6%). 1^-MS (M+H)+=497.0. !H NMR (500 MHz, CDC13) δ ppm 11.53-1 1.67 (1H, m), 8.96 (1H, br s), 7.85-7.96 (1H, m) , 7.38 (1H, s), 7.18 (1H, d, /=8.2 Hz), 7.00-7.16 (4H, m), 4.34 (1H, dd, 7=9.6, 4.4 Hz), 3.83 (3H, s), 3.30-3.57 (6H, m), 3.25-3.29 (1H, m), 3.19-3.26 (1H, m), 2.61-2.72 (1H, m), 2.14-2.25 (1H, m) °

Examples 95A and 95B (S)-N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-N4 , N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine and (R)-N2-(4-(4-chloro-1H-imidazole-1 -yl)-3-methoxyphenyl)-7-(3,4-di 149653.doc -445- 201107311 fluorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H- Cyclopenta[d]pyrimidine-2,4-diamine

Purification of 7^-(4-(4-chloro-1//-imi-l-l-yl)_3_decyloxyphenyl)-7-(3,4-difluorophenyldifluoride) using palmitic SFC _6,7-Dihydro-5//-cyclopenta[d] pain 11 _2,4-diamine: racemic mixture (139 mg, 0.28 mmol, from %), 47.6 11^ peak into (real eve / 95 ^ 4) and 47.3 1118 peak 3 (: |!! P5 million). SFC method: Chiralpak OJ-H (4.6x250 mm, 5 μΜ), (: 02 in 35% 曱Alcohol (〇.1% diethylamine), 35° (: 'flow rate 2. 〇1111//1^11, maintained for 8 minutes, 268 nm absorbance, injection of 5 gL 2 mg/mL solution in methanol (multiple times Stack injection), iR (peak A) = 4.6 minutes, iR (peak β) = 6.3 minutes. The absolute stereochemistry of individual enantiomers (actual 95J and 95β) was not determined. Separation of enantiomers The LC-MS and 1H NMR data were identical to those of the racemic compound (5). Example 96 Ν2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxybenzene Keb 7_(3 4_difluorophenyl)-~Ν-methyl-6,7 -.一风-5 Η-戍弁戍弁[d]嘴.定-2,4 -二月安

F 149653.doc •446- 201107311

2-Chloro-7-(3,4-difluorophenyl)-#-mercapto-6,7-dihydro-5//-cyclopenta[(1]pyrimidin-4-amine (154 mg, 0.521 mmol) was added to 4-(4-chloro-1//-imidazolidinyl)-3-methoxyaniline (175 mg, 0.781 mmol) in EtOAc (2 mL) In solution, the reaction mixture was heated overnight at 120 ° C. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions afforded 2-(4-(4-y-1-I-imidazol-1-yl)-3 -Methoxyphenyl)-7-(3,4-difluorophenyl)indolemethyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine TFA Salt (22.3 mg '0.034 mmo yield 6.46%). LC-MS (Μ+Η)+= 483.2. 4 NMR (500 MHz, CDC13) δ ppm 11.84 (1Η, s), 7.83-7.89 (1Η, m ), 7.55 (1H, s), 7.41-7.46 (1H, m), 7.17- 7.21 (1H, m), 7.10 (2H, s), 6.98-7.05 (2H, m), 5.79-5.90 (1H, m ), 4.38-4.45 (1H, m), 3.85 (3H, s), 3.20-3.25 (3H,

m), 2.90-3.00 (1H, m), 2.70-2.81 (2H, m), 2.20-2.32 (1H, m). Examples 96A and 96B (S)-N2-(4-(4-Chloro-iH-imidazolyl)_3_methoxyphenyl)_7_(3 J-difluorophenyl)-N4-methyl-6,7- Dihydro·5Η-cyclopenta[d]pyrimidine-2,4-diamine and (r)-N2-(4-(4_gas_1H•imidazole-buyl)_3_methoxyphenyldifluoro Phenyl)-indole 4-methyl-6&gt;7-dihydro-5Η_cyclopenta[d]pyrimidine-24-diamine

149653.doc -447- 201107311 Purification using palmitic SFC #2-(4-(4-Ga-1//-Imidazol-1-yl)_3_methoxyphenyl)-7-(3,4- Difluorophenyl)---methyl-6,7-dihydro-5-cyclopenta[d] shouting -2,4-diamine racemic mixture (1.4 L, 2_345 111111〇1 , from the real &quot; disease ^6) 'Get 475 111 peaks eight (real: Yu / Xi ^ 4) and 43 5 111 Danfeng 8 (solid / 9 (55). SFC method: Chiralpak OJ-H (4.6 X250 mm, 5 μΜ), (: 25% sterol (0.1% diethylamine) in 02, 35° 〇 flow rate 2. 〇11^/111111, maintained for 14 minutes, 268 nm absorbance, injection 5 μιη 2 mg/mL Solution in methanol (multiple stack injection), iR (peak Α) = 6.1 minutes, iR (peak B) = 9.2 minutes. The absolute of individual enantiomers (not 9 &lt; 5β) was not determined Stereochemistry. The LC-MS and 1H NMR data of the isolated enantiomers were identical to those of the racemic form. Example 9ΊN2-(4-(4-Ga-1Η-imidazol-1-yl) )-3-methoxyphenyl)-indole 4-methyl-7-(4-(difluoromethoxy)phenyl)-6,7-dihydro-5Η-cyclopenta[d]. D--2,4-diamine

2-Gasylmethyl-7-(4.(trifluoromethoxy)phenyl)_6,7-dihydro·5 seed·cyclopenta[d]pyridin-4-amine (220 mg, 0.640 mmol) Add to a solution of 4-(4- gas-17/-imidazol-1-yl)-3-methoxyaniline (215 mg, 0.960 mmol) in EtOAc (2 mL) The reaction mixture was heated at 80 t: overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions to give; \^_(4·(4-gas-1open·imidazol-1-yl)_3_methoxyphenyl)_ 149653.doc -448- 201107311 methyl-7-( 4-(Trifluoromethoxy)phenyl)-6,7-dihydro-5//cyclopenta[d]pyrimidine-2,4-diamine (92 mg, 0.172 mmol, yield 26.8%). LC-MS (Μ+Η)+=531·2. 4 NMR (500 MHz, CDC13) δ ppm 7.93 (1H, s), 7.66 (1H, br s), 7_50 (1H, s), 7.10-7.23 ( 4H,m), 7.02 (2H, d, J=15.3 Hz), 6.83 (1H, d, J=8.2 Hz), 4.70-4.83 (1H, m), 4.13-4.28 (1H, m), 3.12 (3H , d, J=4.9 Hz), 2.74

(1H, br. s.), 2.65 (2H, d, /=8.2 Hz), 1.97-2.08 (1H, m), 1.25 (3H, s).

Examples 97A and 97B (S)-N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)·Ν, methyl·7-(4-(trifluoromethyl) Oxy)phenyl phenyl 67-dihydro-5 hydrazine - cyclopenta[pyridyl _24_diamine (R)-N2-(4-(4-chloro-1 Η-imidazolyl)_3_methoxyphenyl) _Ν4_methyl 7 (4 (-fluorofoxy)phenyl)·6,7-dihydro-5Η-cyclopenta[d]. Close contact _2,4.

[One

〇, cf3 Purification of W-(4-(4-chloro)methoxyphenyl)- fluorenyl- 7-trifluoromethoxy)phenyl)_6,7_2 gas using a palmitic SFC A racemic mixture of penta[d]pyrimidine-2,4'diamine (80 mg, 〇162 mm〇1 from Shigao 97) gives 36.6 mg peak A (real you 97... and 31 5 149653.doc • 449· 201107311 mg peak B (f Hung 97B). SFC method: Chiralpak OJ-H (4.6x250 mm ' 5 μΜ), 30% sterol (0.1% diethylamine) in C02, 35. 〇, flow rate 2.0 mL /min, maintained for 12 minutes, absorbance at 268 nm, inject 5 μί 2 mg/mL in methanol (multiple stack injections), iR (peak α) = 3.4 min ' iR (peak B) = 7.5 min. Not determined The absolute stereochemistry of the individual enantiomers (Real and E. 75.) The lc-MS and 1 NMR analytical data for the separated enantiomers are identical to those of the racemic (Shen 97). Example 98 Ν2- (4-(4-Ga-1Η-imidazol-1-yl)-3-methoxyphenyl)·Ν4-ethyl-7-(4-(-=~fluoro&gt; methoxy)phenyl) -6,7-dihydro-5Η-cycloindolo[d] σ-bite-2,4-diamine

Pentylene [d] Mouth-4-amine (190 mg, 0.531 mmol) was added to 4-(4-chloro-1//-m-yt-1-yl)-3-methoxyaniline (178 mg, 0.797 mmol) in a solution of acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 90 ° C overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate dissolving fraction 'to give iV2-(4-(4-chloro-1/7-imidazol-1-yl)-3-methoxyphenylethyl-7-(4-(trifluorodecyloxy)benzene 6,7-dihydro-5/f-cyclopenta[d]pyrimidin-2,4- _amine TFA salt (118 mg, 0.174 mmol, yield 32.7%). LC-MS (Μ+ Η)+=545·0. iH NMR (500 MHz, CDC13) δ ppm 11.04 (1Η, s), 9.01 (1H, br s), 8.29 (1H, s), 7.44 (2H, s), will be 2- Gas ethyl-7_(4.(trifluoromethoxy)phenyl)_6,7-dihydro_5//_ ring 149653.doc - 450- 201107311 7.24 (2H, d, J=8.5 Hz), 7.19 (2H, d, J=5.5 Hz), 7.09-7.12 (1H, m), 5.93-5.99 (1H, m), 4.43-4.51 (1H, m), 3.86 (3H, s), 3.62-3.74 (2H , m), 3.46-3.55 (1H, m), 2.85-2.97 (1H, m), 2.71-2.82 (2H, m), 2.26 (1H, m), 1.26-1.41 (3H, m).

Examples 98A and 98B (S)-N2-(4-(4-Chloro-1H-imidazolyl)_3_methoxyphenyl)-N4_ethyl-7-(4-(difluoromethoxy)phenyl )-6,7-dihydro-5U-cyclopenta[d] shouting -2,4-

(R)-N2-(4-(4-Ga-1H-imidazol-1-yl)methoxyphenyl)_N4_ethyl-7-(4-(trifluoromethoxy)phenyl) _67_Dihydro_5H cyclopentapyridine _24_ diamine

Purification of ΛΓ2-(4-(4-Ga-lif-imidazol-1-yl)-3-methoxyphenylmethyl-7-(4-(trifluoromethoxy)phenyl) using palmitic SFC a racemic mixture of -6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine (in mg, 0.204 mmo from CHO 95) gave 29.5 mg of peak A (实/PM) and 37.7 mg peak B (:f do not SFC method: Chiralpak OJ-H (4.6x250 mm, 5 μΜ) '(: 02 in 3〇〇/0 methanol (0.1% diethylamine), 35° C, flow rate 2.0 mL / min 'maintain 12 minutes, absorbance at 268 nm, inject 5 μί 2 45 149653.doc 201107311 W solution in methanol (multiple stack injection), class = 3.4 points • ri r (peak B) 8.2 Knocking. The absolute stereochemistry of the individual enantiomers (Shen and Na) was not determined. The LC-MS and 1H NMR data of the separated enantiomers were identical to those of the racemic form. Example 99 is called 4-(4-chloro-sodium-based)-31-oxyphenyl) 4 (33 diazepamzepine 1 base)-7-(4-(di-imethoxy) stupyl Hydrogen π·cycloindolo[d]pyrimidin-2-amine

〇-cf3 2-O--4-(3,3-difluoroazetidinyl)- 7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5/ /-Cyclopenta[d]pyrimidine (244 mg, 0 601 mm〇i) added to 4-(4-chloro-1//-imidazol-1-yl)_3_decyloxyaniline (2〇2 mg) , 〇 9 〇 2 mmol) in a solution of acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 110 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #-(4-(4-gas-1//-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidine -1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5/ί-cyclopenta[d]pyrimidin-2-amine TFA salt (165.2 mg, 0.229 mmol, yield 38.1%). LC-MS (M+H)+ = 593.3. NMR (500 MHz, CDC13) δ ppm 11.83 (1H, s), 8.00 (1Η, s), 7.38-7.43 (1H, m), 7.30-7.33 (1H, m), 7.27- 149653.doc -452· 201107311 ^ 7·〇9-7.12 (IH, m), 4.76 5 4·9 Hz)^ 3 85 (3H, s), 3.07-m), 2.70-2.81 (2H, m), 2.21- 7.28 (1H, m ), 7.16-7.22 (3H, (1H, br s), 4.46 (1H, dd, 7=9.5 3.17 (2H, m), 2.95-3.04 (2H, 2.34 (2H, m).

Examples 99A and 99B (8) Hi (4-(4-chloro.ta(tetra))• kib 3_methoxyphenyldifluoroazetidinyl·1·yl>·7-(4-(trifluorof-oxygen) Base) phenyl)_6'7 dioxane -

Cyclopenta[d]pyrimidine-2-amine

(R)Hi (4-(4-chloro-oxyphenyl) "(Μ二减环丁丁小基)-7-(4-(trifluoromethoxy)phenyl)·6?- Hydrogen 1 cyclopenta[d]pyrimidine-2-amine

Purification of iV-(4-(4-gas-1 imi-β-s-1 yl)_3 _ methoxyphenyl)-4-(3,3-difluoroazetidinyl) using a neutral SFC _7_(4_(Trifluoromethoxy)phenyl)-6,7-dihydro-5/ί-cyclopenta[d]pyrimidin-2-amine racemic mixture (165.2 mg, 0.279 mmob from f Hungarian pp), obtained 16.7 mg peak A (f Hung 95M) and 17.0 mg peak B (Shen Hung 995). SFC method: Chiralpak OJ-H (4.6x250 mm, 5 μΜ), 30% methanol (0.1% diethylamine) in C02, 35 ° C, flow rate 2.0 mL/min, maintained for 20 minutes, 268 nm absorbance 149653.doc - 453-201107311 degrees, 5 pL of 2 mg/mL solution in methanol (multiple stack injections), (peak A) = 4.9 minutes, iR (peak B) = 15 '〇 minutes. The absolute stereochemistry of individual enantiomers (Shen Hung 9 and 995) was not determined. The LC-MS and 1H NMR data of the isolated enantiomers were identical to those of the racemic (p. p9). Example 100 n2-(4-(4-Ga-1HH1-yl)-3-methoxyphenyl)-N4,N4-difyl-7-(4-(trifluoromethoxy)phenyl)-67 _Dihydro-5H cyclopenta[d]pyrimidine-2,4-diamine

2-Chloro-#,#-dimercapto-7-(4-(trifluorodecyloxy)phenyl)_6,7-dihydro-5//·% pentylene [&lt;1]° 4-Amine (250 mg, 0.699 mmol) was added to 4-(4-va-1//-imidazol-1-yl)-3-methoxyaniline (234 mg, 1.048 mmol) in acetic acid (1 mL) In a solution of THF (1 mL). At 11 baht. (The reaction mixture was heated overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions afforded #-(4-(4- gas-lif-imidazol-1-yl)-3-decyloxyphenyl Dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5/f-cyclopenta[d]pyrimidine-2,4-diamine TFA salt (23 5 Mg,0_3 42 mmobu yield 49.0%). LC-MS (M+H)+= 545.3. NMR (500 MHz, CDC13) δ ppm 11.18-11.39 (1H, m), 8.11 (1H, s), 7.40 -7.45 (1H, m), 7.30-7.34 (1H, m), 7.28 (1H, s), 7.17-7.23 (3H, m), 7.12-7.15 (1H, m), 4.34-4.44 (1H, m) , 3.84 (3H, s), 149653.doc 454- 201107311 3.50 (4H, s), 3.33-3.39 (3H, m), 3.18-3.27 (1H, m), 2.57 2.7 8 (1H, m), 2 · 1 0 - 2 · 3 9 (1H, m ).

Examples 100A and 100B (S)-N2-(4-(4-chloro-1H-imidazolyl-yl)-3_methoxyphenyl)_N4 N4 dimethyl-7-(4-(difluoromethoxy) ) Benki)·6,7·Dihydro-cyclopenta[d]. Condensation 2,4-diamine

(R)-N2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4,N4-dimethyl-7-(4-(trifluoromethoxy) Phenyl)_6,7-dihydro-5Η·cyclopenta[d]pyrimidine,

Purification of 7V2-(4-(4-Ga-1//-Imidazol-1-yl)-3-methoxy by palmitic SFC

Phenylphenyl X#-dimethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine The racemic mixture (235 mg, 0.431 mmol, from the Hungarian 7 00) gave 29.2 mg of peak A (not to 29.2 〇 1 § peak 6 (Purple not 70 〇 5). 8 卩 (: Method: (: 11^如1&lt;:〇]- H (4.6x250 mm ' 5 μΜ), 30% methanol (0.1% diethylamine) in C02, 35 ° C, flow rate 2.0 mL/min, maintained for 1 min, 268 nm absorbance , injection of 5 μί 2 mg / mL solution in sterol (multiple stack injection), (peak Α) = 3 · 7 minutes ' (peak B) = 8 4 minutes. Individual enantiomers were not determined (real Absolute stereochemistry of 7 and 10 (5) 5) Separation of enantiomers LC-149653.doc -455 - 201107311 The MS and 1H NMR analytical data were identical to the racemic (Do not/(10)). Example 101 4-( Azetidin-1-yl,-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy) Phenyl)-6,7-dihydro-5H-cyclopenta[d] shout-2-amine

4-(Azetidin-1-yl)_2_gas-7-(4-(trifluoromethoxy)phenyl)-6.7-dihydro-5/ί-cyclopenta[d]pyrimidine (238 mg, 〇_644 mmol) was added to 4-(4-Gas-1//-imidazol-1-yl)_3_ methoxyaniline (216 mg, 〇 965 mmol) in acetic acid (2 mL) In a solution of 2 mL). The crude reaction mixture was purified by preparative HPLC under heating of the reaction mixture overnight. Evaporation of the appropriate fractions gave 4-(azetidinyl)_#_(4_(4_ gas-1//-imidazole- 1-yl)-3-decyloxyphenyl)-7-(4-(trifluoromethoxy)phenyl)_

6.7-Dihydro-5//·cyclopenta[d]pyrimidin-2-amine TFA salt (99.3 mg '0.148 mmol, yield 22.99%). LC-MS (M+H)+ = 557.2. NMR

7.33-7.40 (1H,m), 7.26 (2H,d, "/=3.1 Hz), 7.17 (3H,s), 7.04 (1H, s), 4.58-4.71 (2H, m), 4.27-4.46 (3H , m), 3.82

(3H, s), 2.91-3.17 (2H, m), (2H, m), 2.14-2.30 (1H, m) 〇 Examples 101A and 101B 2.61-2.74 (1H, m), 2.50-2.60 149653.doc - 456-201107311 〇4-(azetidinyl)·Ν (4_(4-chloro_1H_imidazolyl)-3-methoxyphenyl), 7, (4 (trifluoromethoxy)benzene Dihydrogen 5H cyclopenta[d] 0 crypt-2-amine

Λ (R)-4-(azetidinyl chloride_1Η_imidazole-bu)_3•methoxyphenyl)-7~(4_(trifluorofoxy)phenyl)-67 dihydro _ 5Η_cyclopenta[d] pyridine-2-amine

Purification of 4-(azetidine-bukib#-(4-(4-gas-1//-)&quot;sodium-1-yl)_3_methoxyphenyl)_7_ using palmitic SFC (4_(Trifluoromethoxy)phenyl)-6,7-dihydro-5/f-cyclopenta[d]pyrimidine-2-amine as a racemic mixture (92 mg, 0.165 mmol, from f Chuanxiong, get 37 6 mg peak you Chuan μ)

And 39.1 mg peak Β (#/shore cut 75). SFC method: Chiralpak OJ-H (4.6x250 mm, 5 μΜ) '30% methanol in C02 (〇·1〇/〇diethylamine), 35°C, flow rate 2.0 mL/min, maintained for 18 minutes, absorbance at 268 nm , 5 μί 2 mg/mL solution in sterol (multiple stack injections), /r (peak A) = 4.7 minutes, (peak Β) = 13.6 minutes. The absolute stereochemistry of the individual enantiomers (Examples 101 and 101) was not determined. The LC-MS and 咕 NMR analytical data of the separated enantiomers were identical to those of the racemic (Shiskawa 7). Example 102 Ν2_(4-(4-chloro-1Η-imidazole-4-yl)_3_methoxyphenyl)_7_(3,5•difluorobenzene 149653.doc •457- 201107311 base)-N4-methyl- 6,7-dihydro-5H-cyclopenta[d]a sessile-2,4-diamine

2-Chloro-7-(3,5-difluorophenyl)_#_methyl_6,7-dihydro-5//-cyclopenta[d]pyrimidin-4-amine (60 mg, 0.203 Addition of 4-(4-Gas-1//-imidazol-1-yl)-3-methoxyaniline (68.1 mg, 0.304 mmol) in EtOAc (2 mL) . The reaction mixture was heated at 80 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #2-(4-(4-gas-1//-imidazolyl)_3_methoxyphenyl)-7-(3,5-diphenyl)indolyl-6,7- Dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine TFA salt (33.6 mg, 0.056 mmol, yield 27.5%). LC-MS (M+H) = 483.0. 4 NMR (500 MHz,MeOD) δ δ 7.79 (1H, s), 7.70 (1H, s), 7.29-7.45 (2H, m), 7.22 (1H, d, J=8.5 Hz), 6.86-7.03 (3H, m), 4.27-4.60 (1H, m), 3.89 (3H, s), 3.24-3.48 (5H, m), 3.17 (1H, s), 2.88-3.01 (1H, m), 2.67-2.87 (1H, m), 2.03-2.32 (1H, m). Separation of the racemic mixture by palm chromatography afforded the enantiomers in the form of the free amines, Examples 1-28 and 1023, which have the same spectral data. Example 103 n2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)·Ν4·methyl I49653.doc • 458-201107311 (H5-dichloro-tyl) -6,7 - one wind - 5 H - ring 戍弁 [d] mouth bite -2,4 -diamine

2-Ga-7-V-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5-p-pentylene

[d]°Methyl-4-amine (100 mg, 0.319 mmol) was added to 4-(4-chloro-1//•weiwa-1-yl)-3-decyloxyaniline (1〇7 mg) , 0.478 mmol) in a solution of acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80 ° C overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions gave Λ^·(4-(4-gas-1/f-imidazol-1-yl)-3-methoxyphenyl)-#, methyl-7-(3,4,5- Trifluorophenyl)-6,7-dihydro-5//-cyclopenta[(1] bite- 2,4-diamine butyl? eight salt (3 6.3〇1£'0.057 1!1111〇1 , yield 17.78%). 1^〇MS (M+H)+=501.0. 4 NMR (500 MHz, CDC13) δ ppm 1 1.88-1 1.96 (1H, m), 7.95-8.01 (1H, m), 7.44-7.62 (2H,m), 7.09-7.19 (1H, m), 6.86-6.95 (2H, m), 5.55-5.66 (1H, m), 5.26-5.39 (1H, m), 4.36-4.54 (1H , m), 3.90 (3H, s), 3.22- 3.33 (3H, m), 2.72-2.87 (3H, m), 2.18-2.38 (1H, m).

Examples 103A and 103B (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5- Trifluorophenyl)-6,7-dihydro-51{-cyclopenta[ phenanthroline-2,4-diamine and (R)-N2-(4-(4- gas-1H-imidazol-1- ))-3-methoxyphenyl)-N4_methyl· 149653.doc -459· 201107311 7-(3,4,5-Tritonylphenyl)-6,7·dihydro-5H-cyclopentyl And [d]pyrimidine _2 4 diamine

Purification of iV2-(4-(4-gas-1//_imisin-1-yl)_3_methoxyphenyl)-_/\^-mercapto-7-(3,4) using palmitic SFC ,5-trifluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine racemic mixture (59.8 mg, 〇.i19 mmol, from # &quot;do 703), get 19.5 mg peak A (f you 7 (934) and 34.8 mg peak B (actual / 035). SFC method: Chiralpak OJ-H (4.6x250 mm, 5 μΜ), 20% in C02 Methanol (0.1% diethylamine), 35 ° C, flow rate 2.0 mL / min 'maintained for 16 minutes, 268 nm absorbance, injected 5 pL 2 mg / mL solution in methanol (multiple stack injection), iR (peak A ) = 9.7 minutes, (peak B) = ll_9 minutes. Absolute stereochemistry of individual enantiomers (Situkawa and Kasumi 35) was not determined. LC-MS and 1H NMR analysis of the separated enantiomers Same as the racemate (Essence / 703). Example 1〇4 Ν2-(3-Fluoro-4-(5-methyl-1Η-1,2,4-triazol-1-yl)phenyl) -Ν4-methyl-7 ~(W5,trifluorophenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine

149653.doc -460· 201107311 2-Chloroindolyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5/f_cyclopenta[d]. Methylene-4-amine (65.3 mg, 0.208 mmol) was added to 3-fluoro-4-(5-methyl-1dan-1,2,4-tris(s)-1-yl) strepamine (4 mg) , 0.208 mmol) in a solution of acetic acid (2 mL) and THF (2.0 mL). At 80. The reaction mixture is heated under the armpits. Part of the formation of the desired product was observed. The reaction mixture was heated at 130 ° for 6 hours. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions gave #2-(3-fluoro-4-(3-methyl-1//-1,2,4-triazole)-phenyl)-#4-methyl-7 -(3,4,5-trifluorophenyl)_6,7-dihydro-5-hydroxyl-[d]pyrimidine-2,4-diamine TFA salt (5.3 mg, 8·99 μηιοί, yield 4.32%). LC-MS (Μ+Η)+=470.0.丨H NMR (500 MHz, CDC13) δ ppm 12.17 (1 Η, s), 8.75 (1 Η, d, J = 1.8 Ηζ), 8.05 (1 Η, dd, J=13.7, 2.1 Ηζ), 7.80 (1 Η,t,"7=8.7 Hz), 7.44-7.65 (1 Η, m), 6.74-6.99 (2 H, m), 5.33-5.66 (1 H, m), 4.34-4.67 (1 Η, m) , 3.42-3.74 (2 H, m), 3.29 (3 H, d, /=4.9 Hz), 2.70-2.99 (2 H,m), 2.57 (2 H,s),2.14-2.38 (1 H,m 0 Example 105 N2-(6-(4-Chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N4-methyl-7-(3,4,5-trifluoro Phenyl)-6,7-dihydro·5Η-cyclopenta[d]pyrimidine-2 J-

•461 149653.doc 201107311 2-O-iV-mercapto-7-(3,4,5-trifluorophenyl)_6,7-dihydro-5//_cyclopenta[d]pyrimidine-4 -Amine (100 mg, 0.319 mmol) was added to 6-(4-a-lii-imidazol-1-yl)-5-methoxypyridin-3-amine (1 〇 7 mg, 0,478 mmol) in acetic acid (2 In a solution of mL) and THF (2.000 mL). At 8 〇. The reaction mixture was heated under the armpit overnight. Part of the formation of the desired product was observed. The reaction mixture was heated at 13 (rc) for 6 h. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions afforded iV2-(6-(4-chloro-1//--m- ton).曱oxy 0-pyridin-3-yl)methyl-7-(3,4,5-trifluorophenyl)_6,7-dihydro-5孖-cyclopenta[d] ° 4-Diamine TFA salt (1 2.9 mg, 0.021 mmol, yield 6.50%). LC-MS (Μ+Η)+=502.2 NMR (500 MHz, CDC13) δ ppm 12.33 (1H, s), 8.75 (1H, s), 8.56 (1H, s), 7.61-7.89 (2H, m), 6.85-7.00 (2H, m), 5.62-5.79 (1H, m), 4.36-4.49 (1H, m), 4.02 (3H, s), 3.29 (3H, d, ./=4.9 Hz), 2.88-2.98 (1H, m), 2.76-2.85 (2H, m), 2.21-2.38 (1H, m) 〇Example 1Q6 n2 -(4-(3-chloro-1Η-1,2,4.triazol-1-yl)-3-methoxyphenyl)-N4-f-yl-7-(3,4,5-trifluoro Phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-

2-Ga-indole-methyl-7-(3,4,5-trifluorophenyl)_6,7-dihydro- 5 ugly-cyclopenta[d]°-biti-4-amine (80 mg, 0.255 mmol) was added to 4-(3-chloro-1//-1,2,4-149653.doc •462-201107311 one sit 1 base)-3-methoxyantamine (Μ mg, 0.383 mmol) In a solution of acetic acid (2 mL) and THF (2.0 mL). Heat the reaction mixture overnight at 8 °c. Part of the formation of the desired product was observed. The reaction mixture was heated at l 2 (rc) for 4 hours. The crude reaction mixture was purified by preparative hplc. Evaporation of the appropriate fractions afforded #2-(4-(3-triazol-1-yl)-3-methoxy Phenyl)-#-mercapto-7-(3,4,5-trifluorophenyl)-6,7-dihydrocyclopenta[d] 'π疋-2,4-monoamine TFA salt (15.5 Mg, 0.025 mmol, yield 9.77%). LC-MS (M+H)+= 502.0. NMR (500 MHz, CDC13) δ ppm 11.88-12.12 (1H, m), 8.63 (1H, s), 7.68 -7.81 (1H,m), 7.60 (1H, s), 7.47 (1H,s), 6.92 (1H,t,7=7.2 Hz), 3.94-3.99 (1H, m), 3.52 (8H, s) , 3.22-3.29 (1H, m), 2.87-3.01 (1H, m), 2.74-2.85 (1H, m), 2.22-2.38 (1H, m) 〇 Example 107 N-(4-(4-Chloro-1H) -imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoro. Ratio σ 0-1-yl)-7-(3,4,5-trifluorobenzene -6,7-dihydro-5 H-cyclopenta[d]

2-Chloro-4·(3,3-difluoropyridin-1-yl)-7-(3,4,5-trifluorophenyl)·6,7-dihydro-5//- ring Pentans[d]pyrimidine (105 mg, 0.269 mmol) was added to 4-(4-chloro-1//-0 m 〇-1-yl)-3-methoxyaniline (90 mg, 0.404 mmol) B 149653.doc 463 · 201107311 In a solution of acid (1 mL) and THF (1.000 mL). At 8 〇. (The reaction mixture was heated overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #-(4-(4-chloro-1//--imidazol-1-yl)-3- methoxyl. Phenyl)-4-(3,3-difluoro.pyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-57/-cyclopentyl And [d]pyrimidin-2-amine TFA salt (54.1 mg, 0.074 mmol, yield 27.3%). LC-MS (M+H)+= 577.1. NMR (500 MHz, CDC13) δ ppm 11.70 (1H, s ), 8.08-8.24 (1H, m), 7.40-7.57 (1H, m), 7.18 (1H, s), 6.88-7.01 (2H, m), 4.37-4.45 (1H, m), 4.24-4.35 (2H , m), 4.03-4.22 (2H, m), 3.98-4.03 (1H, m), 3.89 (3H, s), 3.50-3.58 (1H, m), 3.15-3.42 (2H, m), 2.48-2.89 (3H, m), 2.18-2.34 (1H, m).

Examples 107A and 107B (5)-1^-(4-(4-Chloro-11{-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-di-tunpyridine- 1-yl)-7-(3,4,5-trifluorophenyl)-6J-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (r)-N-(4-(4- Gas-1H-imidazol-1-yl)-3-methoxyphenyl)_4_(3i3-difluoro 0-Butyl-1-yl)-7-(3,4,5-trifluorophenyl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

149653.doc -464 - 201107311 Purification of Λ^(4-(4-chloro-1//-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-) using palmitic SFC Difluoropyridin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5//-cyclopenta[d]pyrimidin-2-amine The racemic mixture (48 mg, 0.083 mmol, from real 1 &quot;07) gave 19.8 mg peak A (Purple 7 and 17.2 mg peak B (Shiyouchuan 75). SFC method: Chiralpak OJ-H (4.6 x 250) Mm, 5 μΜ), 25% methanol (0.1% diethylamine) in C02, 35 ° C, flow rate 2.0 mL/min, maintained for 30 minutes, 268 nm absorbance, injection of 5 μί 2 mg/mL solution in sterol (multiple stack injections), iR (peak Α) = 17.4 minutes, (peak Β) = 21.2 minutes. Individual enantiomers were not determined (Essence/7074 and its absolute stereochemistry. Separated enantiomers) The LC-MS and .4 NMR analytical data were identical to those of the racemate (Zi Xi/7 07). Example 108 ]^-(4-(4-Chloro-11{-imidazol-1-yl)-3-methyl Oxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H- Cyclopenta[d]pyrimidin-2-amine

2-Chloro-4-(3,3-difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5-open- Cyclopenta[d]pyrimidine (105 mg, 0.279 mmol) was added to 4-(4- gas-1-imidazol-1-yl)-3-nonanoylanilide (94 mg, 0.419 mmol) in acetic acid (1) In a solution of mL) and THF (1.000 mL). At 8 〇. 149 149653.doc •465·201107311 The reaction mixture was heated overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate dissolving fraction 'to give #-(4-(4-气-1//--salt-1-yl)-3-indolyloxyphenyl)-4-(3,3-difluoroazetidine Alkan-1-1yl)·7-(3,4,5-trisylphenyl)-6,7-dihydro-5//-cyclopenta[d]mouth alpha-2-amine TFA salt (31.4 Mg, 0.044 mmol, yield 15.60%). LC-MS (Μ+Η)+=563·1. NMR (500 MHz, CDC13) δ ppm 1187 (m, s), 8.09 (1H, s), 7.45 (1H, dd, /=8.5, 1.5 Hz), 7.36 (1H, s), 7.29 (2H, s) , 7.25 (1H, d, J=S.5 Hz), 7.16 (1H, s), 6.91 (2H, t, 7=6.9 Hz), 4.40 (1H, dd, J=9.2, 4.9 Hz), 4.00 ( 1H, s), 3.89 (3H, s), 3.53 (1 H, s), 3.08-3.19 (1H, m), 2.97-3.06 (1H, m), 2.72-2.84 (1H, m), 2.26 (1H , td, 7 = 9.2, 4.3 Hz). Example (10) N2-(4-(4-Chloro-1H-imidazol-1-yl)_3_decyloxyphenyl)-7-(2,4-difluorophenyl)-N4-methyl-6,7- Dihydro-5H-cycloindolo[d]*»密"定-2,4-diamine

2- gas-7-(2,4-difluorophenyl)1-methyl-6,7-dihydro-5/ί_cyclopenta[d]pyrimidin-4-amine (184.6) in a capped vial Mg, 0.624 mmol) and 4-(4-Gas-1//-imidazo-butyryl)-3-nonyloxyaniline (HO mg, 0.624 mmol) in THF (1095 μM and acetic acid (1095 pL) The solution was heated overnight at 80 ° C. The solvent was evaporated <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjj 201107311 The organic extract was dried and dried over anhydrous sulphuric acid. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford #2-(4-chloro-1 //-Imidazol-1-yl)-3-methoxyphenyl)_7·(2 4_difluorophenyl)methyl-6,7-dihydro-5//-cyclopenta(4) _2,4-Diamine (179.6 mg, 0.372 mmo yield 59.6%). LC-MS (Μ+Η)+=483·1.

H NMR (500 MHz, CDCI3) δ ppm 7.97 (1H, d, J=2.1 Hz), 7.49 (1H, d, J=\.5 Hz), 7.01-7.10 (2H, m), 7.00 (1H, d , J=1.5 Hz), 6.73-6.84 (3H, m), 4.44 (1H, s), 3.61 (3H, s), 3.11 (3H, d, J=4.9 Hz), 2.59-2.77 (2H, m) , 1.95-2.05 (2H, m).

Examples 109A and 109B (S)-N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)·7_(2,4-difluorophenyl)-indole 4-A Base-6,7-dihydro-5Η-cyclopenta[d]feed 2,4-diamine(R)-N2-(4-(4-chloro-1Η-imidazol-1-yl)-3 -foxyphenyl)-7-(2,4-difluorophenyl)44-fluorenyl-6,7-dihydro-51{-cyclopenta[(1] mouth bite-2,4-diamine

Purification of 妒-(4-(4-Ga-1//-imidazol-1-yl)-3-methoxyphenyl)-TV¥-triterpenoids using palmitic supercritical fluid chromatography (SFC) a racemic mixture of _7_phenyl_6,7-dihydro-5 仏cyclopenta[d]pyrimidine-2,4-diamine (18 〇 mg, 0.206 mmol, from f Chuan 9) Obtained 28·4 mg peak A (f 149653.doc 467· 201107311 and 27.4 mg peak B (f ^^(995). SFC method: &lt;^^1卩&amp; let 〇:^ 11 (21 parent 250 〇 1111'5 41^)'(: 02 in 350 /. sterol (〇.10 / 〇 diethylamine), 35 ° C 'flow rate 45 mL / min, maintain ι〇 min, 268 nm absorbance, injection 0.75 mL 20 Mg/mL in decyl alcohol (multiple stack injections), iR (peak A) = 3.6 minutes ' iR (peak B) = 7.2 minutes. Individual enantiomers were not determined (real eve / 7 and / still The LC-MS and 1H NMR analytical data of the enantiomers of the absolute stereochemical oxime separation are the same as those of the racemate (Example). Example 110 Ν2-(4-(4-chloro-1Η- Imidazolyl-1-yl)-3-methoxyphenyl)_ then _ethyl_7-methyl-7-phenyl-6,7-dihydro-5 fluorene-cyclopenta(4) ν 唆_2, 4-diamine

The preparation Va was prepared by the method of Example 74, and the product was obtained from the product of the product of the formula V. -Methoxyphenyl)-N4-ethyl-7-methyl-7-phenylamino-6,7-dihydro-5H_cyclopenta[d]carcinoma-2,4-diamine (Example 11〇 ). Lc_ms (M+H)+=475.2. 4 NMR (500 MHz, methanol, to) δ ppm 8 〇3 (1 H, d, /=2.14 Hz), 7.65 (1 H, s), 7.22-7.30 (4 H, m), 7.20 (1 H, s), 7.10-7.16 (2 H, m), 7·02 (1 η, dd ^/=8 55 2 14

Hz), 3.66 (3 H, s), 3.56 (2 H, q, J=7.32 Hz), 2.56-2.69 (2 H,m), 2.30-2.38 (1 H,m),2.14-2.22 (1 h , m), 1.25 (3 H d • /= 7.20 Hz). 149653.doc -468· 201107311 The isolation of the racemic mixture by grass chromatography was carried out to give the enantiomers Examples 11 0A and 11 0B, both having the same spectral data. Example 111 N2-(4-(4-Gas-1H-miso-s-l-yl)-3-indolylphenyl)--4-ethyl-7-dilyl-7-phenyl-6,7 -dihydro-51{-cyclopenta[(^]〇$〇定-2,4-diamine

HN~

K

The preparation Wa was combined with 4-(4-gas-1H-miso-1 -yl)-3-methoxyaniline (Preparation A) using the method of Example 74 to give N2-(4-(4-chloro-) 1H-imidazol-1-yl)-3-methoxybenzyl)-N4-ethyl-7-dipropyl-7-phenyl-6,7-diaza-5 pentazino[(1]pyrimidine -2,4-Diamine (Example 111). [(:-]\48(]^+11)+= 501.2. NMR (500 MHz, CDC13) δ ppm 11.66 (1 H, br. s.), 7.45 -7.54 (2 H, m), 7.32-7.39 (5 H, m), 7.25-7.30 (3 H, m), 5.57-5.68 (1 H, m, J=16.94, 9.92, 7.17, 7.17 Hz), 5.42 (1 H, br. s.), 5.22 (1 H, d, 7=16.17 Hz), 5.12 (1 H, d, J=10.07 Hz), 3.85 (3 H, s)5 3.63-3.70 (2 H, m), 3.05-3.12 (2 H, m), 2.64-2.80 (2 H, m), 2.51-2.63 (2 H, m), 1.35 (3 H, t, «/=7.17 Hz) ° Example 112 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)·8_(3 5-diphenyl)-:^4_ethyl-7,8 -dihydro-51{-pyrano[4,3-pharo-pyrimidine-2,4-diamine

TFAM 149653.doc -469- 201107311

〇 NH

2-Ga-8-(3,5-Difluorophenyl)-N-ethyl-7,8-dihydro-5H-piperac[4,3-d]pyrimidin-4-amine (Preparation xa (87 mg, 0.267 mmol), 4-(4-Gas-1H-imidazol-1-yl)-3-methoxyanilide (Preparation A) (71.7 mg, 0.321 mmol), bis(dibenzylideneacetone) ) palladium (0) (12 23 mg, 〇·013 mmol), (9,9-dimercapto-9Η-dibenzopyran-4,5-diyl)bis(diphenylphosphine) (15.45 mg) , 〇 〇 〇 27 mmol) and sodium carbonate (42.5 mg, 0.401 mmol) in dioxane (1272 μΙ〇 / water (254 μιη) mixture was heated overnight at 110 ° C. The reaction mixture was diluted with water and EtOAc The combined organic layers were washed with brine and concentrated in vacuo. EtOAc EtOAc EtOAc (EtOAc: EtOAc EtOAc Column: PHENOMENEX LUNA 21x100 mm '10uC18, flow rate: 25 ml/min, 30%-100% B, 20 minutes) to purify the crude product to obtain N2-(4-(4- gas-1H-imidazole-1- 3-benzyloxyphenyl)-8-(3,5-difluorophenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine -2,4-diamine TFA salt (Example 112) (123 mg, 0.177 mmol, Yield 66.1%) LC-MS (M+H)+=513.2. 4 NMR (500 MHz, CDC13) δ ppm 11.71 (s, 1 Η) 8.04 (s, 1 Η) 7.49 (d, J=2.14 Hz , 1 H) 7.43 (dd, J=8.55, 2.14 Hz, 1 H) 7.23 (d5 J = 8.55 Hz, 1 H) 7.17 (d, J=1.53 Hz, 1 H) 7.00 (d, J=5.80 Hz, 2 H) 6.70-6.84 (m, 1 H) 6.09 (t, J=5.19 Hz, 1 H) 4.73 (d, J=14.34 149653.doc •470· 201107311

Hz&gt; 1 Η) 4.54 (d, J = 14.34 Hz, 1 H) 3.95-4.15 (m, 3 H) 3.88 (s,3 H) 3.61_3.78 (m,2 H) 1.37 (t, J=7.17 Hz, 3 H). The racemic mixture was isolated by palm chromatography to give the enantiomers U2A and 112B as free amines. LC-MS (M+H)+ = 513 2. NMR (500 MHz, MeOD) δ ppm 7.84 (d, J = 2.14 Hz &gt; 1 H) 7.67 (d, J = 1.53 Hz, 1 H) 7.21 (d, J = 1.53 Hz, 1 H) 7.13 (d, J =8.55 Hz, 1 H) 6.98-7.08 (m, 1 H) 6.89 (d, J=2.14

Hz&gt; 1 H) 6.74-6.85 (m, 1 H) 4.65 (d, J=14.34 Hz, 1 H) 4.46-4.59 (m,1 H) 4.11 (dd, J=11.44,4.43 Hz, 1 H) 3.96 (dd, J=11.44, 4.12 Hz, 1 H) 3.88 (d, J=3.97 Hz, 1 H) 3.66 (s, 3 H) 3.58 (q, J=7.32 Hz, 2 H) 1.27 (t, J= 7.17 Hz, 3 H). Example 113 N2-(4-(4-Ga-1H-imidazolylmethoxyphenyl)-8-(34-dimorphylphenyl)-N4-ethyl-7,8-dihydro-5H-pyrano[ 4,3-d]pyrimidine-2,4-diamine TFA salt

2-Ga-8-(3,4-difluorophenyl)_N_ethyl_7,8-dichloro_5h•Bud [4,3-d]pyrimidine_4_amine (Preparation Ya) Reaction with 4_(4_gas_m-imidazolyloxyaniline (Preparation A) as described in Example 112 gave n (4_(4Lu 1Η^1·yl)-whatyloxyphenyl)句^二气phenyl149653.doc •471 · 201107311 N4-ethyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine TFA salt (Example 113 LC-MS (Μ+Η)+=513·5. 'H NMR (500 MHz, MeOD) δ ppm 7.84 (d, J=1.22 Hz, 1 H) 7.58 (d, J=2.14 Hz, 1 H 7.32-7.49 (m, 3 H) 7.12-7.32 (m, 3 H) 4.71 (d, J=14.95 Hz, 1 H) 4.55 (d, J=14.65 Hz, 1 H) 4.14 (dd, J=11.60) , 4.27 Hz, 1 H) 4.06 (br. s., 1 H) 3.92-4.02 (m, 1 H) 3.89 (s, 3 H) 3.68-3.70 (m,2 H) 1.32 (t, J=7_17 Hz , 3 H).

Separation of the racemic mixture by palm chromatography afforded the enantiomers 113A and 113B as free amines. LC-MS (M+H)+= 513.3. 4 NMR (500 MHz,MeOD) δ.ρριη 7.83 (d,J=2.14

Hz, 1 H) 7.67 (s, 1 H) 7.09-7.25 (m, 4 H) 6.96-7.09 (m, 2 H) 4.59-4.69 (m, 1 H) 4.47-4.57 (m, 1 H) 4.10 ( Dd, J=11.29, 4.27 Hz, 1 H) 3.92 (dd, J=11.60, 4.27 Hz, 1 H) 3.86 (d, J=3.36 Hz, 1 H) 3.62-3.68 (m, 3 H) 3.57 (q , J = 7.32 Hz, 2 H) 1.22-1.34 (m, 3 H). Example 114

N-(4-(4·Gas-1H-imidazole-uyl)_3•methoxyphenyl)4_(3 3 difluoroazetidin-1-yl)-8-(3,4-di Fluorophenyl)_7,8-dihydro-5H-pyrano-i4j_d]pyrimidin-2-amine TFA salt

149653.doc •472· 201107311

2chloro-4-(3,3-difluoroazetidinyl-i_yl)_8_(3,4-difluorophenyl)_ 7,8-one gas ~5Η-Π 喃[4, 3-d]pyrimidine (Preparation Yb) and 4-(4-Ga-1H-m-s-l-yl)-3·methoxyaniline (Preparation A) reacted as described in Example 112 to give N_(4 -(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(3,3_-fluoroazetidine-indoleyl)_8_(3,4-difluoro Phenyl)-7,8-dihydro-5H_° benzo[4,3-d]pyrimidinamine TFA salt (Example 114). LC-MS (M+H) = 561.5. NMR (500 MHz, CDC13) δ ppm 12.12 (br. s., 1 H) 7.80 (s, 1 H) 7.38 (dd, J=8.55, 1.83 Hz, 1 H) 7·2〇-7.3ΐ (m, 4 H) 7.09-7.18 (m, 2 H) 4.69-4.89 (m,6 H) 4·06 (m,3 H) 3.87 (s,3 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 114a and 114B as free amines. LC-MS (M+H)+ = 561.3. NMR (500 MHz, MeOD) δ ppm 7.74 (s,1 Η) 7 66 (s,1 Η) 7.10-7.24 (m,4 Η) 7.08 (d,J=1.53 Hz, 1 Η) 7.02 (ds j= G.55 Hz, 1 H) 4.76-4.84 (m, 1 H) 4.68 (d, J=14.〇4 Hz, 1 H) 4.59 (t, J=12.21 Hz, 4 H) 4.14 (dd, J_u. 29, 3.66 Hz, 1 H) 3.98 (br. s., 1 H) 3.86-3.94 (m, 1 H) 3.59 (s, 3 H). Example 115 N2~(4_(4_Chloro)^-imidazolyl-3-methoxyphenyldioxaphenyl)-indole 4-methyl-7,8-dihydro-5 H- britylene 4,3-d]pyrimidine-2,4-diamine

TFAM 149653.doc -473- 201107311

2-Ga-8-(3,4-difluorophenyl)_N_methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Yc Reaction with 4_(4 gas_1H imidazolylyl)_3_decyloxyaniline (Preparation A) as described in Example 12 to give N2_(4-(4-chloro-1H-imidazolyl)_3_ Methoxyphenyl)8(3,4 difluorophenyl)_ Ν 4-mercapto-7,8-dihydro-5-pyrido[4,3-d]pyrimidine-2,4-diamine TFA salt (Example 115). LC-MS (Μ+Η)+=499·5. NMR (500 ΜΗζ,

MeOD) δ ppm 7.86 (d, J=1.53 Hz, 1 H) 7.66 (d, J=2.14 Hz, 1 H) 7.26-7.41 (m, 4 H) 7.17.7.25 (m, 2 H) 4.70 (d, J=14.65 Hz&gt; 1 H) 4.54 (dd, J=14.95, 1.53 Hz, 1 H) 4.15 (dd, 1=11.60, 4.27 Hz, 1 H) 4.07 (br. s., 1 H) 3.96 (dd, J=11.60, 3.36 Hz, 1 H) 3.89 (s, 3 H) 3.16 (s, 3 H). The separation of the racemic mixture by palm chromatography gave the enantiomers of the free amines as examples 115A and 115B. LC-MS (M+H)+ = 499 3. NMR (5 〇〇 MHz, MeOD) δ ppm 7.90 (d, J = 2.14 Hz, 1 H) 7.67 (d, J = 1.53 Hz, 1 H) 7.12-7.25 (m, 4 H) 7.07 (d, J=2.14 Hz,1 H) 6.98-7.05 (m,1 H) 4.63 (d,J=14.34 Hz, 1 H) 4.45-4.57 (m,1 h) 4.11 (dd,J=ll.44,4.43 Hz , 1 H) 3.93 (dd, Bu 11.44, 4 43 Hz, 1 H) 3.87 (d, J = 3.97 Hz, 1 H) 3.61-3.7 〇 (m, 3 h) 3.00-3.08 (m, 3 H). Example 116 149653.doc •474- 201107311 8_(3,4-difluorophenyl)_N4_ethyl-:^2_(3_fluoro_4_(5·methyl_1H_12,4_1) base)- 7,8-一虱- 5H-Brigade [4,3-d] bite-2,4-diamine TFA salt

2-Chloro-8-(3,4-difluorophenyl)_N_ethyl-7,8-dihydro-5Η·piperid[4,3-&lt;1]. Bite_4_amine (preparative core) and 3_fluoro_4_(5-methyl-111-1,2,4-triazol-1-yl)aniline (preparation c) occurred as described in Example 112 The reaction gives 8_(3,4-difluorophenyl)-indole 4-ethyl-indole 2-(3_fluoro-4-(5-methyl-ml, 2,4-trisyl) base)-7 , 8 -Dihydro-5H- 0 benzo[4,3-d] mouth bites the 2,4-diamine TFA salt (Example 116). LC-MS (M+H)+ = 482.3. 'H NMR (500 MHz, MeOD) δ ppm 8·!3 (s, 1 Η) 7.95 (dd, J=12.36, 1.98 Hz, 1 H) 7.47-7.62 (m, 2 H) 7.30-7.42 (m, 1 H) 7.23-7.30 (m, 1 H) 7.21 (br. s., 1 H) 4.72 (d5 J=14.95 Hz, 1 H) 4.55 (d, J=14.95 Hz, 1 H) 4.14 (dd, J =ll.44s 4&gt;12 Hz, 1 H) 4.07 (br. s., 1 H) 3.91-4.01 (m, 1 H) 3.58-3.75 (m,2 H) 2.44 (s,3 H) 1.26-1.43 (m, 3 H). The racemic mixture was isolated by palm chromatography to give the enantiomers U6A and 116B as free amines. LC-MS (M+H)+ = 482.3. NMR 4 NMR (500 MHz, MeOD) δ ppm 8.05 (d, J = 2.14 Hz, 1 H) 8.03 (s, 1 H) 7.27-7.34 (m, 2 H) 7.17-7.25 149653.doc •475· 201107311 ( m, 2 Η) 7.12 (d, J—1.83 Hz, 1 H) 4.61-4.68 (m, 1 H) 4.56 (t, 1 = 14.19 Hz, 1 H) 4.15 (dd, J=11.29, 4.58 Hz, 1 H) 4.00 (dd, 1=11.44, 4.73 Hz, 1 H) 3.90 (d, J = 4.27 Hz, 1 H) 3.58- 3.66 (m,2 H) 2.38 (s,3 H) 1_19 (t,J= 7.02 Hz, 3 H). Example 117 N2-(4-(4-Ga-1H-m-m-yl-1-yl)-3-methoxyphenyl)-]^4-((}1)_1_cyclopropylethyl)- 8-(4-(Trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine TFA salt

2-Chloro-N-((R)-1-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3 -d]pyrimidine-4-amine (preparative Zc) and 4_(4_qi_out·taste.sodium-1-yl)-3-decyloxyaniline (preparation A) were reacted as described in Example 112. , N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4_((R)-l-cyclopropylethyl)·8·(4_(three) Fluorinyl)phenyl)7 8 dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine TFA salt (Example 1). LC-MS (M+H)+= 585.4. 4 NMR (500 MHz, CDC13) δ ppm 11.95 (s,1 Η) 7.68 (d, J=i.53 Hz, 1 H) 7.52-7.65 (m, 4 H) 7.31-7.43 (m5 2 H) 7.16-7.22 (m, 1 H) 7.10 (d, 1 = 1.53 Hz, 1 H) 5.62 (t, J = 7.02 Hz, 1 H) 4.75 (dd, J=14.34 , 4.88 Hz, 1 H) 4.58 (dd, J=13.89, 8.39 Hz, 1 H) 4.11 (d, J=2.14 Hz, 3 H) 3.73-3.91 149653.doc -476- 201107311 (m, 4 Η) 1.40 (dd, J=10.38, 6.71 Hz, 3 H) 1.06 (ddd, J=7-78, 3.05, 2.90 Hz, 1 H) 0.69 (dt, J=8.62, 4.39 Hz, 1 H) 0.51-0.64 (m , ih) 0.38 (ddd, J=14.50, 9.77, 4.73 Hz, 1 H) 〇·32 (dd, j=9.6l, 4.73 Hz, 1 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 117A and 117B as free amines. LC-MS (M+H)+ = 585.1. NMR (500 MHz, MeOD) δ ppm 7.73 (d, J = 2.14 Hz, 1 H) 7.56-7.68 (m, 3 H) 7.44 (d, J = 8.24 Hz, 2 H) 7.19 (d, J = 1.53 Hz , 1 H) 7.09 (d, J=8.55 Hz, 1 H) 6.94 (dd, J=8.55, 2·14 Hz, 1 H) 4.65-4.72 (m,1 H) 4.52-4.62 (m,1 H) 4.16 (dd, J=11.44, 4.73 Hz, 1 H) 3.92 (dd, J=11.29, 4.88 Hz, 1 H) 3.89 (dd, J=8.24, 6.71 Hz, 1 H) 3.49 (s, 3 H) 3.06 (q, J=7.32 Hz, 1 H) 1.22-1.41 (m, 3 H) 1.08 (dt, J=8.24, 4.88 Hz, 1 H) 0.51-0.59 (m, 1 H) 0.48 (dd, J=8.39 , 5.04 Hz, 1 H) 0.39 (dd, J = 9.77, 4.58 Hz, 1 H) 0.19-0.33 (m, 1 H). Example 118. N2-(4-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-8-(4-(trifluoromethyl)phenyl) _7,8·Dihydro·5H_pyrano[4,3_d]pyrimidine_2,4-diamine TFA salt

149653.doc -477-201107311 2-Vethylethyl-8-(4-(trifluoromethyl)phenyl)7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine The compound Za) was reacted with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyantamine (Preparation A) as described in Example 112 to give Ν2·(4-(4- Gas-1H-imidazolium-yl)_3_methoxyphenyl)_N4_ethyl_8_(4-(difluoroindolyl)phenyl)-7,8-dihydro-5H-pyrano[4] , 3-d]pyrimidine-2,4-diamine TFA salt (Example 118). LC-MS (M+H)+=545.3. 4 NMR (500 MHz, CDCl3) δ mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp mp 7.49 (d, J=2.14 Hz, 1 H) 7.40 (dd, J=8.55, 2.14 Hz, 1 H) 7.20 (d, J=8.55 Hz, 1 H) 7.11 (d, J=1.53 Hz, 1 H) 6.38 (br. s·,1 H) 4.76 (d, J=14.34 Hz, 1 H) 4.57 (d, J=13.73 Hz, 1 H) 4.07-4.16 (m,3 H) 3.86 (s,3 H) 3.59-3.77 (m, 2 H) 1.36 (t, J = 7.17 Hz, 3 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 118A and 118B as free amines. LC-MS (M+H)+ = 545.1.咕 NMR (500 MHz, MeOD) δ ppm 7.79 (d, J=l 83

Hz,1 H) 7.56-7.70 (m,3 H) 7.43 (d,J=7.93 Hzs 2 H) 7.19 (d, J=l.53 Hz, 1 H) 7.11 (d, J=8.55 Hz, 1 H 6.91-7.03 (m 1 H) 4.60-4.72 (m,1 H) 4.48-4.60 (m,1 Η) 4·15 (dd J=11.14, 4.43 Hz, 1 H) 3.99 (t, J=4_27 Hz ,1 Η) 3·87·3 97 (m,1 H) 3.46-3.66 (m,5 H) 1.28 (t,J=7.17 HZ,3 H) 〇Example 119 N4-Ethyl-N2-(3- Fluoro-4-(5-methyl-1H-1,2,4-triazolyl) benzoic acid 8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-piperidin Methane [4,3_d] a bite-2 4, diamine TFA salt 149653.doc 478- 201107311

2-Chloro-indole·ethyl-8-(4-(trifluoromethyl)phenyl)·7,8-dihydro-5H-pyrano[4,3-d] (Preparation Za) was reacted with 3-fluoro-4-(5-methyl-1H-1,2,4-tris(yt-1-yl)aniline (preparation c) as described in Example 112 to give N4-ethyl-N2-(3-fluoro-4-(5-fluorenyl-1h_i,2,4-triazol-1-yl)phenyl)-8-(4-(trifluoromethyl)phenyl _7,8-Dihydro-5H_* oxo[4,3-d]pyrimidine-2,4-diamine TFA salt (Example 119). LC-MS (Μ+Η).=514·3. 4 NMR (500 MHz, CDC13) δ ppm 12.20 (br. s., 1 H) 8.01 (s, 1 H) 7.93 (dd, J=12.36, 2.29 Hz, 1 H) 7.59 (m, 4 H) 7.52 (dd, J=8.85, 1.53 Hz, 1 H) 7.38 (t, J=8.39 Hz, 1 H) 5.97 (br. s., 1 H) 4.72 ( d, J=14.34 Hz, 1 H) 4.54 (d, J=13.73 Hz, 1 H) 3.99-4.18 (m, 3 H) 3.57-3.75 (m, 2 H) 2.43 (s, 3 H) 1.37 (t , J = 7.17 Hz, 3 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 119A and 119B as free amines. LC-MS (M+H)+ = 514.1. NMR (500 MHz, MeOD) δ ppm 8.02 (s,1 Η) 8.00 (dd, J=14.04, 2.14 Hz, 1 H) 7.62 (m, J=8.24 Hz, 2 H) 7.48 (m, J=8.24 Hz , 2 H) 7.21-7.34 (m, 2 H) 4.62-4.72 (m, 1 H) 4.52-4.62 (m, 1 H) 4.15-4.27 (m, 1 H) 3.94-4.09 (m, 2 H) 3.58 (q, j=7.32 Hz, 2 H) 2.36 (s, 3 H) 1.30 (t, J=7.17 149653.doc -479· 201107311

Hz, 3 Η). Example 120 Ν2-(4-(4-Chloro-1Η-imidazole a-yl)_3_methoxyphenyl)N4 f*_8_(4-(difluoromethyl)phenyl)-7,8-dihydrogen ·5H piperido[43d]pyrimidine_24_diamine TFA abundance

2-Chloro-N-mercapto-8(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Zb) Reaction with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) as described in Example 112 to give N2-(4-(4- gas-1H) -. Mizozol-1-yl)_3_decyloxyphenyl)_N4_fluorenyl_8_(4-(difluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4, 3-d]pyrimidine-2,4-diamine TFA salt (example no). LC-MS (M+H)+ = 531.3. NMR (500 MHz, CDC13) δ ppm Π.80 (s, 1 Η) 7.87 (d, J=1.53 Hz, 1 H) 7.51-7.63 (m, 5 H) 7.40 (dd, J=8.85, 2.14 Hz, 1 H) 7.28 (s, 1 H) 7.20 (d, J=8.55 Hz, 1 H) 6.56 (d, J=4.58 Hz, 1 H) 4.76 (d, J=14.34 Hz, 1 H) 4.57 (d, J=14.04 Hz, 1 H) 4.01-4.14 (m, 3 H) 3.87 (s, 3 H) 3.21 (d, J=4.58 Hz, 3 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 120A and 120B as free amines. LC-MS (M+H)+ = 531.1. NMR (500 MHz, MeOD) δ ppm 7.86 (d,J=2.u 149653.doc -480- 201107311 ^ 1 Η) 7.65 (d, 1=1.53 Hz, 1 H) 7.60 (m, J.7.93 Ηζ, 2 H) .43 (m, J = 7.93HZ, 2H) 719 (d, W. 53HZ, 1H) 7.11 (d, =8-55h2s1H) 6.96 (dd, j=8.55j 2.14HZ}1H) 4 59_4 6g =,1H) H)4 l5(dd,(iv)i 29, (π Hz i &gt;3^-4.〇3 (m,1H)3.92 (dd5 1=11.29, 4.88 Hz, 1H) 3.52 (S,3 H 3·〇4 (s, 3 H). Example 121

_(2"-Gas-ΙΗ-Misinyl)-methoxyphenylamino) 4 (B, monohydro- 5H-Nantido[4,3-d]pyrimidine _8·yl) Guess the salt

CN

*4-(2-lacty-4-(ethylamino)_7,8-dihydro-5H_-flavored [4,3_d]-indole-8_ soil)-benzonitrile (preparation AAa) and 4- (4-Chloro-1H-moxisin-1-yl)_3_decyloxyaniline (Preparation A) was reacted as described in Example 112 to give 4_(2_(4-chloro-1H-imidazole-1) -yl)_3_methoxyphenylamino)_4_(ethylamino)_7 8_dihydro-5H-piperazo[4,3-d]pyrimidin-8-yl)benzonitrile TFA salt (Example 121 ). LC-MS (M+H)+=502.3. 4 NMR (500 MHz, CDC13) δ PPm 11.80 (s, 1 H) 7.93 (s, 1 H) 7.61-7.66 (m, 2 H) 7.55-7_61 (m , 2 H) 7.48 (d, J = 1.83 Hz, 1 H) 7.41 (dd, J=8.55, 2.14 Hz, 1 H) 7.22 (d, J=8.85 Hz, 1 H) 7.15 (d, J=1.53 Hz , 1 H) 6.22 (t, J=5.34 Hz, 1 H) 4.76 (d, J=14.34 Hz, 1 H) 149653.doc •481· 201107311 4.57 (d, J=i4.34 Hz, 1 H) 4.09 (s, 3 H) 3.87 (s5 3 H) 3.66-3·75 (m, 2 H) 1.37 (t, J = 7.32 Hz, 3 H). Separation of the racemic mixture by palm chromatography gave the enantiomers 121A and 121B as free amines. LC-MS (M+H)+ = 5 〇 2.1. 'H NMR (500 MHz, MeOD) δ ppm 7.80 (d, J = 2.14 Hz, 1 Η) 7·67 (d, J = 2.14 Hz, 2 H) 7.66 (br. s·, 1 H) 7.45 (d , 1=8.24 Hz, 2 H) 7.22 (s, 1 H) 7.13 (d, J = 8.55 Hz, 1 H) 6.98-7.05 (m, 1 H) 4.62-4.69 (m, 1 H) 4.51-4.57 ( m, 1 H) 4.15 (dd, J=l〇.993 3.97 Hz, 1 H) 3.91-4.02 (m, 2 H) 3.54-3.64 (m,5 H) 1.28 (t, J=7.17 Hz, 3 H ). ΤΗ 122 N2_(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-(4-(trifluoromethoxy)phenyl)-78 _Dihydro-5H-pyrano[43d]pyrimidine-2,4-diamine

To 2- gas fluorenyl-8-(4-(trifluorodecyloxy)phenyl)_7,8-dihydro-5H_piperidinan[4,3-&lt;1]»密11定_4 -Amine (69.8 11^, 0.194 111111〇1), 4-(4-Gas-111-m-nar-1-yl)-3-methoxyaniline (Preparation a) (52.1 mg, 0.233 mmol), XANTPHOS (ll.23 mg, 0.019 mmol), Pd2(dba)3 (8.88 mg, 9.70 μπιοί) and Cs2CO3 (190 mg, 0.582 mmol) mixed 149653.doc •482· 201107311 Adding dioxins (808 pL) ). The mixture was flushed with nitrogen and placed in a capped vial at 1 Torr. Heat your armpits overnight.

The reaction was cooled to room temperature and diluted with EtOAc. Filter through a diatomaceous earth plug and spin evaporate. The residue was taken on a silica gel eluting with EtOAc/Hex gradient to afford N2-(4-(4- </RTI> &lt;RTI ID=0.0&gt; -(4-(Trifluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine. LC-MS (Μ+Η)+=547·2. 4 NMR (500 MHz, CDC13) δ ppm 7.78 (1 H, s), 7.48 (1 Η, s), 7.25-7.29 (2 Η, m), 7.11-7.20 (2 Η, m), 6.94-7.09 (3 Η, m), 6.77 (1 Η, d, ^=8.55 Hz), 4.50-4.67 (2 H, m), 4.32 (1 H, d, 7=4.88 Hz), 4.07-4.19 (1 H, m), 3.89-4.01 (2 H, m), 3.52 (3 H, s), 3.09 (3 H,d,&gt;7=4.58 Hz). Separation of the racemic mixture by palm chromatography gave the enantiomers of both of the examples 122A and 122B' having the same spectral data.

Examples 123A and 123B N-(4-(4-chloro-1H-miso-I-yl)-3-methoxyphenyl)-4-((R)-3-fluoro. Base)-8-(4~(trisethoxy)phenyl)-7,8-diode-511-0 base and [4,3-d]pyrimidin-2-amine

149653.doc • 483 - 201107311 Individual diastereomers to 2-chloro-4-((R)-3- ° ratio ° ̄-1-yl)-8-(4-(trifluoromethoxy) Phenyl)-7,8-dihydro-5H-piperacino[4,3-d]pyrimidine (57.6 mg, 0 138 mmol), 4-(4-Gas-1H-imidazol-1-yl) _3_decyloxyaniline (preparative A) (37.0 mg, 0.165 mmol), XANTPHOS (7.98 mg, 0.014 mmol), Pd2 (dba) 3 (6.31 mg, 6.89 μπιοί) and Cs2C03 (135 mg '0.414 mmol) Dioxane (574 called) was added to the mixture. Rinse the mixture with air and place in a capped vial and heat overnight at 1 °C. The reaction was cooled to room rt and diluted with EtOAc EtOAc EtOAc. The residue was taken on EtOAc (EtOAc) elute elute 123A: LC-MS (Μ+Η)+=605·3. H NMR (500 MHz, MeOD) δ ppm Ί.19 (1 Η, d, J=1.53 Hz), 7.46-7.53 (3 H, m), 7.32-7.41 (4 H, m), 7.19 (1 H , dd, /=8.55, 2.14 Hz), 5.43 (1 H, d, 7=52.50 Hz), 5.12-5.18 (1 H, m), 4.99 (1 H, d, /=14.34 Hz), 3.98-4.33 (6 H, m), 3.87 (3 H, s), 3.81 (1 H, dd, /=10.68, 6.41 Hz), 2.37-2.49 (1 H, m), 2.15-2.33 (1 H, m). 123B: LC-MS (M+H)+ = 605.3. iH NMR (500 MHz, CDC13) δ ppm 7.56 (1 H, d, J=1.B3 Hz), 7.48 (1 H, d, «7=1.53 Hz), 7.22-7.28 (2 H,m), 7.14 (2 H,d,*7=8.24 Hz), 7.04 (1 H, d, /=8.55 Hz), 6.99 (1 H, d, J=l.22 Hz), 6.82 (1 H, dd, J= 8.55, 1.83 Hz), 5.33 (1 H, d, 7=52.80 Hz), 4.90- 149653.doc -484 - 201107311 5·〇〇(2 Η, m), 4.16-4.26 (1 Η, m)5 4.10 (1 Η, dd, J=Ui44 4'43 ΗΖ), 3·8〇-4·〇1 (5 Η, m), 3.50 (3 Η, s), 2.32-2.43 (1 Η m), 2.00- 2.19 u Η, m). Example 124 Ν -(4-(4-Ga-indole-imidazolium)-3-methoxyphenyl)-Ν4_ethylmethyl-8-phenyl-5,6,7,8-tetrahydropyrene嗤琳_2,4-diamine 〇

To 2 chloro-#-ethylmercapto-8-phenyl-5,6,7,8-tetrahydroquinazoline-4-amine (42·9 mg, 0.142 mmol) and 4-(4-gas- 1//-imidazole_ι_yl)·3_ oxime anilide (31.8 mg, 0142 mm 〇1) in THF (2 mL) was added 6% by weight of sodium hydride in mineral oil suspension (6.82 mg, 0.284) Mm). The reaction mixture was heated at 80 ° C for 1 to 5 hours with stirring in a capped vial. The reaction mixture was carefully partitioned between aqueous ammonium chloride and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried and transitioned through a waterless stone town. The solvent was removed in vacuo and the residue was purified mpjjjjjjjjjj #4-乙-iV4-曱基-8·phenyl-5,6,7,8-tetrazolium 坐°坐和&gt;-2,4-diamine (31.6 mg '0.048 mmol, yield 33.5% 〇LC-MS (M+H)+=489.2 ° !H NMR (500 MHz, CDC13) δ ppm Π.50 (1H, br s), 7.74 (1H, d, J=1.2 Hz), 7.39 (1H , dd, /=8.5, 2.1 Hz), 7.29 (2H, dd, J=4.9, 2.7 Hz), 7.21-7.27 149653.doc -485 · 201107311 (2H,m), 7.12-7.19 (3H, m), 7·07 (1H,d, VII·5 Hz), 4·20 (1H, t, J=7.0 Hz), 3.80 (3H, s), 3.68-3.78 (2H, m, 7=13.8, 7.0, 7.0, 7.0, 7.0 Hz), 3.31 (3H, s), 2.64-2.82 (2H, m), 2.27 (1H, ddd, 7=13.3, 7.5, 5.2 Hz), 1-88-1.99 (1H, m) , 1.74- 1,85 (1H, m), 1.54-1.67 (1H, m), 134 (3H, % piece Hz).

Examples 124A and 124B (3)-:^2-(4-(4-Chloro-1}{-imidazol-1-yl)-3-methoxyphenyl)-#-ethyl-]^4-A -8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine oxime (r)-N2-(4-(4-Ga-1Η-imidazol-1-yl) -&gt; methoxyphenyl)-Ν4_ethyl_ Ν4-methyl-8-phenyl-5,6, 7,8-tetrahydroindenyl-2,4-diamine

Purification of #2-(4-(4-Ga-1/ί-imidazol-1-yl)-3-methoxyphenyl)-#4-ethyl using palmitic supercritical fluid chromatography (SFC) a racemic mixture of -iV4-methyl-8-phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine (183 mg, 0.206 mmol 'from Shi 724) 54.7 mg peak A (real 72 heart 4) and 53.3 mg peak B (purple 7 to 5). SFC method: Chiralpak OJ-H (30x250 mm, 5 μΜ) 'C02 medium 3〇〇/0 sterol (〇.ι〇/0 diethylamine), 35 ° C, flow rate 70 mL / min, maintain 1 〇 5 Minutes, 22 〇 nm absorbance, injection of 75.75 mL of 26 mg/mL solution in methanol (multiple stack injections), iR (peak A) = 4. 9 minutes, peak B) = 12.0 minutes. Individual enantiomers were not determined 149653.doc •486· 201107311 Constructs (real///72 and absolute stereochemistry. LC-MS and 1H NMR analysis of isolated enantiomers and racemates The same sentence is given. Example 125 ]^-(4-(4-Chloro-11{-i-S-n-l-yl)-3-methoxyphenyl)_8-phenyl_ 5,6,7,8-tetra Hydroquinone-2-amine

2-Gas-8-phenyl-5,6,7,8-tetrahydroindole (33.0 mg, 0.135 mmol) and 4-(4-gas-1Η-imidazole-1 in a 2.0-5.0 mL microwave tube To a solution of benzyloxy-3-phenyloxyaniline (33-2 mg '0.148 mmol) in THF (1.5 mL) was added 0.5 M KHMDS in benzene (0-809 mL, 0.405 mmol). The tube was sealed and the reaction mixture was stirred at 100 ° C for 2 hours in a microwave. The reaction mixture was diluted with decyl alcohol and purified using reverse phase preparative HPLC. The solvent was removed in vacuo and the residue was purified by reverse phase preparative HPLC to afford of 4-(4-chloro-1 </RTI> &lt;RTI ID=0.0&gt;Base)-#4-ethyl-#4-methyl-8-phenyl-5,6,7,8-tetrahydroindenyl-2,4-diamine (31.6 mg, 0.048 mmol, yield 33.5 %). LC-MS (M+H)+ = 432.3. NMR (500 MHz, CDC13) δ ppm 11.68 (1H, s), 8-25 (1Η, s), 8.14 (1H, s), 7.32-7.39 (3H, m), 7.26-7.32 (1H, m), 7.05-7.12 (3H, m), 6.96-7.04 (2H, m), 4.20 (1H, t, Hz), 3.41 (3H, s), 2.80-2.94 (2H, m), 2.30-2.40 (1H, 149653 .doc -487- 201107311 m), 1.97-2.12 (2H, m), 1.81-1.93 (1H, m). Example 126 N2-(4-(4·Chloro-1H-.methane-1-yl)-3-methoxyphenyl)-n4-ethyl-8-(4-fluorophenyl)-N4-methyl -5,6,7,8-tetrahydroquinazoline 2,4-diamine

N gas, hydrazine 2-methoxyethyl-8-(4-fluorophenyl)-#-methyl-5,6,7,8-tetrahydroquinazoline-4-amine (124 mg, 0.388 mmol) Add to 4-(4-chloro-1//-°m-yt-1-yl)-3-decyloxyaniline (87 mg, 0.388 mmol) in THF (1 mL) and acetic acid (1.000 mL) In solution. The reaction mixture was stirred at 75 ° C overnight. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to give #2-(4-(4-chloro-1//-imidazol-1-yl)-3-decyloxyphenyl)-#qiethyl-8-(4-fluorophenyl) )-#-Mercapto-5,6,7,8-tetrahydroquinazoline-2,4-diamine TFA salt (101.3 11^, 0.153 111111 〇1, yield 39.5%). ;1(:-]\^(^1+11)+= 507.2 ° 】H NMR (500 MHz, CDC13) δ ppm 10.77-11.01 (1H, m), 7.95-8.15 (1H, m), 7.33-7.44 (1H, m), 7.22-7.24 (1H, m)5 7.19 (1H, d, 7=8.5 Hz), 7.12-7.16 (2H, m), 6.96-7.03 (2H, m), 4.09-4.21 (1H , m), 3.96 (1H, s), 3.81 (4H, s), 3.67-3.79 (3H, m), 3.32 (3H, s), 2.19-2.33 (1H, m), 1.88-1.99 (1H, m ), 1.71-1.81 (1H, m), 1.56-1.69 (1H, m), 1.26-1.38 (3H, m). Example 12Ί 149653.doc •488· 201107311 N2-(4-(4-Chlorine-1H- Imidazo-buki)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,N4-dimethyl-5,6,7,8-tetrahydroquinazoline-2,4 -diamine

°'-ΛΓν

2-Chloro-8-(4-fluorophenyl)-#,-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine (118 mg, 0.386 mmol) was added to 4- (4-Chloro-1//-m., -1-yl)-3-decyloxyaniline (95 mg, 0.424 mmol) in THF (1 mL) The reaction mixture was stirred at 75 ° C overnight. The crude reaction mixture was purified by preparative HPLC. Evaporation of the appropriate fractions gave 2-(4-(4-chloro-1//-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-iV, iV4 -Dimethyl-5,6,7,8-tetrahydrofuran, sitting on the 2,4-diamine Eight salts (74.8 mg, 0.123 mmol' yield 31.9%). LC-MS (M+H)+ =495. !H NMR (500 MHz, CDC13) δ ppm 11.69 (1Η, s), 7.59 (1H, d,·Ζ_1·2 Hz), 7.36 (2H,d, "7=2.1 Hz), 7.14 (3H, d, «/=9 2

Hz), 7.05 (1H, d, J=1.5 Hz), 6.99 (2H, s), 4.17-4.27 (1H, m), 3.81 (3H, s), 3.47 (1H, s), 3.36 (5H, s ), 2.65-2.84 (2H, m), 2.21-2.33 (1H, m), 1.87-1.98 (1H, m), 1.69-1.81 (1H m), 1.53-1.67 (1H, m).

tH127A^ 127B (S)-N2-(4-(4-chloro-1H-imidazole-i-yl)_3_methoxyphenyl)_8_(4-fluorophenyl)-N4,N4-dimethyl- 5,6,7,8-tetrazole quinoxaline-2,4-diamine and 149653.doc -489- 201107311 (R)-N2-(4-(4-chloro-1H-imidazole small group μ, A Oxyphenyl) Winter (4-fluorophenyl)-N4,N-monomethyl-5,6,7,8-tetrahydroindole. Isolate-2,4-diamine

Purification using palmar SFC#, (4-(4-Ga-1//-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-#,#- Dimercapto-5,6,7,8-tetrahydroquinazoline- 2,4-diamine racemic mixture (actual /27), peak (Α 727d) and peak B (real) 5 Do not 7275). SFC method: Chiralpak OJ-H (4.6 &gt;&lt; 250 mm ' 5 μΜ), 30% methanol (0.1% diethylamine) in C02, 35 ° C, flow rate 2_0 mL/min, maintained for 13 minutes, absorbance at 268 nm , 5 μί 2 mg/mL solution in sterol (multiple stack injections), &amp; (peak Α) = 4 3 minutes 'Q (peak Β) = 9.6 minutes. The individual enantiomers were not determined (the absolute stereochemistry was removed and the LC-MS and 4 NMR data of the separated enantiomers were identical to those of the racemic (萦BΜ7). Example 128 N (4-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)_8_(4-fluorophenyl)_ 5,6,7,8-tetrahydroindole-2- amine

F 149653.doc •490· 201107311

2-Chloro_8_(4·fluorophenyl)-5,6,7,8-tetrahydrocarbazol (20 mg' 0.076 mmol) and 4-(4-gas- in a 2.0_5.0 mL microwave tube A solution of 0.5 M KHMDS (0.167 mL, 0.084 mmol) was added to a solution of lif-imidazol-1-yl)-3-methoxyaniline (18.73 mg '0.084 mmol) in THF ( 1.5 mL). The tube was sealed and the reaction mixture was stirred at 100 ° C for 2 hours in a microwave. The reaction mixture was diluted with decyl alcohol and purified using preparative HPLC. The appropriate fractions were evaporated to give #-(4-(4-chloro-li/-imidazol-1-yl)-3-methoxyphenyl)-8-(4-φ-phenyl)-5,6, 7,8-Tetrahydroquinazolin-2-amine TFA salt (0.7 mg, 1.229 μηιοί ' yield: 1.614%). LC-MS (M+H)+=450.2. 4 NMR (500 MHz, CDC13) δ ppm 8.14-8.26 (1H, m), 7.56-7.62 (1H, m), 7.43-7.48 (1H, m), 7.28 -7.31 (1H,m), 7.21 (1H,s), 6.98-7.10 (6H, m), 6.88-6.94 (1H, m), 4.08-4.18 (1H, m), 2.77-2.83 (3H,m) ,2.23-2.32 (1H,m),1.91-2.13 (3H,m), 1.25 (1H,s) 〇Example 129 • N2-(4-(4-Ga-1H-imidazol-1-yl)-3- Methoxyphenyl)-N4-methyl-6-(methyl26-branched)-8-phenyl-5,6,7, 8-tetrahydro 0-bite [4,3-d] mouth bite- 2,4~ diamine

Diisopropylethylamine (0.11 g, 0.867 mmol) was added to a solution of the preparation AEj (0.2 g' 0.433 mmol) in hexanes at -10 C, followed by 149653.doc -491 - 201107311 Chlorofluorene (0.055 g, 0.477 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dioxane, washed with water and evaporated under reduced vacuo. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Phenyl)-N4-mercapto-6-(indolyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-(1]pyrimidine-2,4-diamine (0.105 g, 48%). LC-MS (Μ+Η)+=540·2. NMR (400 MHz, DMSO-J5): δ ppm 9.20 (1H, s), 8.03 (1H, s), 7.72 ( 1H, s), 7.41 (1H, s), 7.31-7.03 (8H, m), 4.21 (1H, m), 4.11 (2H, m), 3.60-3.47 (5H, m), 2.96 (3H, d, J = 4.4 Hz), 2.89 (3H, s). This example was isolated by palm chromatography to give the enantiomers 129A and 129B, which have the same spectral data. Example 130 N2-(4- (4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropyl sulphate)-B-methyl-8-phenyl-5,6&gt;7,8- Tetrahydropyrido[4,3-(1]pyrimidine-2,4-

To a solution of the preparation AEj (0.32 g, 0.693 mmol) in dioxane, diisopropylethylamine (0.18 g, 1.38 mm 〇i) was added at -10 C, followed by 149653.doc -492· 201107311 Cyclopropyl stone helium (0.117 g '0.832 mmol). The reaction mixture was searched for 1 hour at room temperature. The reaction mixture was diluted with di-methane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative hplc (yield of EtOAc (1% EtOAc). Oxyphenyl) 6-(cyclopropyl % mercapto)-N4-mercapto-8-phenyl-5,6,7,8-tetrahydro. ratio. And [4,3-d]pyridin-2,4-diamine (O.il g, 35%). LC-MS (Μ+Η)+=566·0. Ih NMR (400 MHz, DMSO-^): δ ppm 9.18 (1H, s), 8.03 (1H, s), 7.72 (1H, s), 7.40 (1H, s), 7.31-7.04 (8H, m), 4.26 (1H, m), 4.10 (2H, m), 3.68 (1H, m), 3.68-3.65 (4H, m), 2.98 (3H,d, «7=4.4 Hz), 2.54 (1H, m), 0.95 (4H, m). This example was isolated by palm chromatography to give the same spectral data for both enantiomers l3〇A and 130B'. Example 131 2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-di Hydrogen pyrido[4,3-d] rabbit bite-6(5H)-formic acid methyl vinegar

CI

To a solution of the preparation AEk (0.15 g, 0.3 mmol) in dioxane, diisopropylethylamine (0.081 g, 0.6 mmol) was added at -1 0 C, followed by methyl chloroformate (0.044 g) , 0.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dioxane, washed with water, 149 EtOAc. Purification of the crude compound by preparative HpLC (H.sub.1H.曱oxyphenylaminoethylamino)8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-decanoic acid decyl ester (0.12 g &gt; 68%) 〇Lc.ms (mH)+=532.2 〇'H NMR (400 MHz, DMS〇,: δ 啊9·16 (1H, s), 7.98 (1H, s), 7.73 (1H, s), 7-42 (1H, s), 7.29-7.26 (2H, m), 7.21-7.12 (5H, m), 7.05 (1H, m), 4.62 (ih, m), 4.23 (1H, m), 3.96-3.87 (3H , m), 3.68-3.51 (8H, m), 1.23 (3H, t, J = 8.0 Hz) 分离 This example is isolated by palm chromatography to give the enantiomers 13 and 13 1B ' Both have the same spectral data. Example 132 (2-(4-(4-Ga-1H-imidazole-bu))-methoxyphenylamino)4(ethylamino)-8-phenyl- 7,8-dihydropyrido[4,3-d]pyrimidine-60H-cyclopropylpropyl fluorenone

To a solution of the preparation AEk (0.35 g, 0.73 mmol) in di- methane at -10 ° C, diisopropylethylamine (〇.14 g, M mm〇1) was added followed by cyclopropyl carbonyl (0.085 g, 0.81 mmol) 〇 The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water and evaporated and evaporated. The crude compound was purified by preparative HPLC (yield: 149 149. 3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-(1]pyrimidin-6(511)- (cyclopropyl)fluorenone (0.12 g, 30%). LC-MS (Μ+Η), 544·2.] H NMR (400 MHz, CDC13(5): δ ppm 7.70 (1Η, s) , 7.51 (1H, s), 7.31-7.23 (3H,m), 7.12-6.99 (4H,m), 6.93 (1H,6s), 5.05 (1H, m), 4.22 (1H, m), 4.07 (1H , m), 3.99 (1H, m), 3.63 (1H, m), 3.59 (5H, m), 1.33 (3H, t, J=7.2 Hz), 1.25 (1H, m), 0.87 (1H, m) , 0.84 (2H, m), 0.63 (1H, m). This example was isolated by palm chromatography to give the enantiomers 13 2 A and Π 2 Β, both having the same spectral data. Example m 1 -(2-(4-(4-chloro-1 Η-味°-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7 8-Dihydroindole ° and [4, 3-d]. milidine -6 (5 Η)-yl)-2-methoxyethyl ketone

Triethylamine (0.79 g '0.78 mmol) was added to a solution of the preparation AEk (0.187 g, 0.39 mmol) in dioxane at -10 ° C, followed by the addition of decyloxy oxime (0.043 g) , 0.42 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water and evaporated with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-(2-(4-(4-Chloro-1H-imidazol-yl)-)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7, as an off-white solid. 8-Dihydropyrido[4,3-d]pyrimidin-6(5Η)-yl)-2-decyloxyethanone (0.10 g, 57%). LC-MS (Μ+Η)+ = 548·2. 4 hiMR (400 MHz, DMSO-must): δ ppm 9,19 (1Η, s), 7.99 (1Η, s), 7_73 (1H,1), 7.42 (1H, s), 7.32-7.09 (8 H, m), 4.86 (1H, m), 4.20 (2H, m), 4.09 (2H, m), 4.02-3.50 (5H, m), 3.31 (1H ,m), 3.18 (1H,m), 2.99 (3H,s), 1.23 (3H,t,*7=7.2

Hz). This example was isolated by palm chromatography to give the same spectral data for both enantiomers 133A and 133B'. Example 134 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-f-oxyphenyl)44-ethyl-6-(methylsulfonyl)-8-phenyl-5,6 ,7,8-tetrahydropyrido[4,3-d]pyrimidine-2&gt;4-diamine

Add diisopropylethylamine (0.054 g, 〇42 mmol) to a solution of the preparation AEk (0.10 g, 0.21 mmol) in dioxane at -1 〇C, followed by the addition of strontium sulphate (0.024 .g ' 0·21 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with di-methane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc: EtOAc EtOAc EtOAc EtOAc )-3-methoxyphenyl)_N4-ethyl 6 (methyl s sulfenyl) _8_phenyl _5 6,7,8·tetrahydropyrido[buprofen _ 2,4-diamine (0.06 g, 鄕). LC-MS (M+H)+ = 554.0.咕NMR (400 MHz, DMS〇-^&lt;5): δ ppm 9.17 (1H, s), 7.96 (1H, s), V.73 (1H, s), 7.42 (1H, s), 7.32-7.20 (5H, m), 7.16-7.10 (2H, m), 6.98 (iH, m)5 4.22 (1H, m), 4.11-4.03 (2H, m), 3.62-3.49 (7H, m), 2.91 (3H , s), 1.23 (3H, t, J = 7.2 Hz) 分离 This example was isolated by palm chromatography to give the same spectral data for both enantiomers 134A and 134B'. Example 13 5 chloro-iH-imidazole _i_yl)_3_f-oxyphenylamino)_4 (ethylamino)-8-phenyl-7,8-dihydroacridino[4,3-dioxin -6(511)-yl)-2-(dimethylamino)ethyl ketone

Triethylamine (0.079 g, 0.78 mmol) was added to a solution of the preparation AEk (0.15 g, 0_3 mmol) in dioxane at -10 C, followed by the addition of N,N-dimethylamino ethane. Hydrochloride (0.054 g, 〇·34 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water and evaporated evaporated Purification of the crude compound by preparative HPLC (acetonitrile containing 0.1% aqueous ammonium acetate)

〇I 149653.doc -497- 201107311 1-(2-(4-(4-)·1Η-imidazol-1-yl)-3-decyloxy-based fe)-4-(B) Amino)-8-phenyl-7,8-dihydrogen ratio bite [4,3-d]17 唆-6(5H)-yl)-2-(diamido)ethanone (0.11 g, 72%) 〇LC-MS (M+H)+= 561.2. 4 NMR (400 MHz, DMSO-m): δ ppm 9·16 (1H, s), 7.98 (1H, s), 7.72 (1H , s), 7.40 (1H, s), 7.31-7.11 (7H, m), 7.07 (1H, m), 4.77 (1H, m), 4.06 (2H, m), 3.94 (1H, m), 3.60 ( 1H, m), 3.52-3.42 (5H, m), 2.72 (1H, m), 2.28 (1H, m), 2.15 (6H, s), 1.20 (3H, m). This example was isolated by palm chromatography to give the same spectral data for both enantiomers i 3 5 A and 13 5B '. Example 136 N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-6-(cyclopropyl-decyl)-N4-ethyl-8-phenyl -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-

Diisopropylethylamine (0.77 g, 0.62 mmol) was added to a solution of the preparation AEk (0.15 g, 0.31 mmol) in dichlorohydrazine at -10 °C, followed by the addition of cyclopropane (醢). 0.042 g, 0.3 1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with a methylene chloride, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative HPLC (methanol containing hydrazine - 1% acetic acid aqueous solution) to give a gray

149653.doc -498· 201107311 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-6-(%-propyl aryl) in the form of a color solid -N4-ethyl-8-phenyl-5,6,7,8-tetrahydrogen ratio. And [4,3·d]pyrimidine-2,4-diamine (0.10 g, 55%). LC-MS (Μ+Η)+=578.2. 'Η NMR (400 MHz, CDC13): δ ppm 9.15 (1H, s), 7.95 (1H, s), 7.72 (1H, s), 7.41 (1H, s), 7.29 (2H, m), 7.21 (3H ,m), 7.14 (2H, m), 7.01 (1H, bs), 4.26 (1H, m), 4.11 (2H, m), 3.65 (1H, m), 3.56-3.51 (6H, m), 2.5 ( 1H, m), 1.23 (5H, m), 0.97 (2H, m). This example was isolated by palm chromatography to give the enantiomers i 3 6 A and 136B, both having the same spectral data. Example 137 1-(2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(ethylamino)-8-phenyl-7, 8-Dihydro. Bipyrido[4,3-d]pyrimidine-6(5H)-yl)B_

Diisopropylethylamine (0.77 g, 0.62 mmol) was added to the solution of the preparation AEk (0.15 g, 0.31 mmol) in di- methane at -1 ° C, followed by the addition of acetonitrile (0.027 g) , 0.31 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dioxane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Oxyphenylamino)-4-(B 149653.doc -499- 201107311 Amino)-8-phenyl·7,8-dihydro. Bipyridyl[Double-...pyrimidine^^-- Ethyl ketone (〇.〇9 g . 570/0) 〇LC-MS (M+H)+=518.2 〇Ή NMR (400 MHz, DMSO-^): δ ppm 9.19 (1H, s), 8.00 〇Η, s), 7.74 (iH} s), 7-42 (1H, s), 7.28 (3H, m), 7.17-7.07 (5H, m), 4.91 (1H, m), 4.06 (1H, m), 3.93 (1H, m), 3.82 (2H, m), 3.58-3.50 (5H, m), 1.47 (3 H, s), 1.23 (3H, m) 分离 Separate this example by palm chromatography The enantiomers 137 and 13 7B 'have the same spectral data. Example 138 # N2-(4-(4-Gas-1H-imidazol-1-yl)-3-methoxyphenyl)-N4_ethyl-6-(ethylhistyl)-8-phenyl-5 ,6,7,8-tetrahydropyrido[4,3-pharo-pyrimidine-2,4-diamine

Diisopropylethylamine (〇·77 g, 0.62 mmol) was added to a solution of the preparation AEk (0.15 g, 0.3 1 mmol) in dioxet at -10 C, followed by the addition of ethanesulfonate ( 0.038 g, 0.31 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dioxane, washed with water and evaporated evaporated The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Oxyphenyl)-N4-ethyl-6-(ethyl fluorenyl)-8-phenyl-5,6,7,8-tetrahydrogen ratio α[4,3-d] bite - 149653.doc • 500· 201107311

2,4-diamine (0.11 g, 62%). LC-MS (MH)+=566.2. 4 NMR (400 MHz, DMSO-J5): δ ppm 9.17 (1H, s), 7.96 (1H, s), 7.73 (1H, s), 7.42 (1H, s) , 7.31 (2H, m), 7.28 (3H, m), 7.21 (2H, m), 6.97 (1H, m), 4.25 (1H, m), 4.13-4.05 (2H, m), 3·60 (1H , m), 3.58-3.50 (6H, m), 3.05 (2H, m), 1-23 (3H, t • 7 = 8.0 Hz), 1.17 (3H, t, *7 = 7.2 Hz). This example was isolated by palm chromatography to give the enantiomers 13 8 A and 138B, both having the same spectral data. Example 139 N4-ethyl-N2-(3·fluoro-4_(L-methyl 6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine-2,4-

To a solution of the preparation AEm (0.20 g, 0.450 mmol) in dioxane at -10 C, diisopropylethylamine (〇 11 g, 〇 9 〇 mmol) was added, followed by the addition of hydrazine (0.05 g '0.450 mmol). The reaction mixture was mixed for 1 hour at room temperature. The reaction mixture was diluted with dioxane, washed with water &lt The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) -6-(曱sulfonyl)_8_phenyl_5,6,7,8_tetrahydro 0-pyridine and [4,3_d] 149653.doc -501 ^ 201107311 Pyrimidine-2,4-diamine (0.048 g, 20%). LC-MS (M+H)+ = 523.2. NMR (400 MHz, OUSO-d6): δ ppm 9.44 (1H, s), 8.67 (1H, s), 8.00 (in, m), 7.42 (2H, m), 7.39 (2H, m), 7.32 (3H , m), 7.05 (1H, m), 4.20 (1H, m), 4.08 (2H, m), 3.63 (1H, m), 3.55-3.46 (3H, m), 2.92 (3H, s), 2.33 ( 3H, s), 1.24 (3H, t, */=7·2 Hz) 分离 This example was isolated by palm chromatography to give the same spectral data for both enantiomers 139A and 139B'. Example 140 N4-Ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)- 8-phenyl-5,6,7,8-tetrahydropyrido[4,3-(1]pyrimidine-2,4-diamine

To a solution of the preparation AE (0.25 g, 0.560 mmol) in dichloromethane was added diisopropylethylamine (0.145 g, 1.120 mmol) at -1 ° C, followed by the addition of methanesulfonate (〇 ·〇6 g, 0.560 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene methane and washed with water &lt The crude compound was purified by preparative EtOAc EtOAc (EtOAc:EtOAc 2,4-Triazol-yl)phenyl)-6-(nonylsulfonyl)-8-phenyl-5,6,7,8-tetrahydro.比 并 [4,3-d] 149653.doc -502- 201107311 ° 唆-2,4-diamine (0.05 §, 22%). ! ^8(^4-1:1)+=521.2. 111 NMR (400 MHz, DMSO-^6): δ ppm 9.47 (1H, s), 8.00 (2H, m), 7.44 (1H, m), 7.33-7.22 (6H, m), 7.05 (1H, m), 4.21 (1H, m), 4.11-4.07 (2H, m), 3.63 (1H, m), 3.57-3.50 (3H, m), 2· 93 (3H, s), 2.27 (3H, s), 1.24 (3H, t, «7=7.2 Hz). This example was isolated by palm chromatography to give enantiomers 140A and 140B, both having the same spectral data. Example 141 6-(Cyclopropylsulfonyl)-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)·Ν4-A -8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

To a solution of the preparation AE1 (0.23 g, 0.534 mmol) in di- methane was added diisopropylethylamine (0.138 g, 1.060 mmol), then cyclopropanesulfonate ( 0.089 g, 0·640 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with water and evaporated evaporated The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Methyl-1H-1,2,4-triazole-1.yl;)phenyl)_N4-methyl-8-phenyl-5,6,7,8-tetrahydropyridinium [4,3 -d]pyrimidine-2,4-diamine (0.11 g, 50%) °LC-MS (M+H)+= 149653.doc •503-201107311 535.2. 4 NMR (400 MHz, DMSO-M)·· δ ρρΐΏ 9.45 (1H, s), 8.68 (1H, s), 8.03 (1H, m), 7.22 (2H, m), 7 32_7 η (5H, m), 7.11 (1H, m), 4.25 (1H, m), 4.13 (1H, m), 4.08 (1H, m), 3.71 (1H, m), 3.64 (1H, m), 2.96 (3H, d, J=4.〇Hz), 2.58 (1H, m ), 2.33 (3H, s)5 1.01-0.95 (4H, m) 分离 This example was isolated by palm chromatography to give the enantiomers 丨4丨A and 141B, both having the same spectral data. . Example 142 6-(cyclopropyl fluorescein)-N2-(3-fluoro-4-(5-methyl-iH-1,2,4-triwax-yl)phenyl)-N4-A -8-phenyl-5,6,7,8-tetrahydropyrido[4,3_d]-pyridyl-indole, 4-diamine

Add diisopropylethylamine (〇18〇g, 139 mmol) to a solution of the preparation AEm (0.30 g, 0.690 mmol) in dioxane at -1 〇C, followed by cyclopropanesulfonate (0 117 g, 〇83〇mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water &lt The crude compound was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) -mercapto-1H-1,2,4.triazol-1-yl)phenyl)-N4-mercapto-8-phenyl-5,6,7,8-tetrahydropyridyl[4,3 -d] Pyrimidine-2,4-diamine (0.14 g, 45%). LC-MS (M+H)+= 149653.doc 201107311 535.2. 4 NMR (400 MHz, DMSO-hand): δ ppm 9.49 (1H s) 8.02 (2H, m), 7.46 (1H, m), 7.44 7.33 (3H,m),7 3〇_7 21 (3H, m), 7.11 (1H,m), 4.26 (1H,m), 4.15 (ih, m),4 1〇(1H,m),3.73 (1H,m),3.59 (1H,m),3·28 (3h,m),2 59 (1H,m), 2.27 (3H,s),1.24-1.0 (4H,m) 〇Example 143 Jade Propyl (4-(ethylamino)-2-(3- gas-4-(3-methyltridecyl)-ylamino)-8-phenyl-7,8-di-tO-[a] -d] mouth bite _6(5H)-yl) fluorenone

To a solution of the preparation AEm (0.21 g, 0.49 mmol) in hexanes, was added diisopropylethylamine (〇· 12 g, 0.70 mmol) at -10 ° C, followed by cyclopropyl groups Chlorine (0.056 g, 0.54 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dioxane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) 4-(3-methyl-1H-1,2,4-tridec-1-yl)phenylamino)-8-phenyl-7,8-dihydropyridinium[4,3-d Pyrimidine -6(5H)-yl)methanone (0.090 g, 38%). LC-MS (Μ+Η)+=513·4. 4 NMR (400 MHz, CDC13 &lt;5): δ ppm 8.41 (1Η, s), 7.94 (1Η, m), 7.63 (1H, m), 7.32 ( 3H, m), 7.27 (1H, m), 7.10 (2H, m), 149653.doc - 505 - 201107311 4.97 (1H, m), 4.21 (1H, m), 4.10-4.0 (2H, m), 3.91 (1H,m), 3.63 (2H,m), 2.48 (3H,s), 1.35 (3H,t,/=7.2 Hz), l 22 UH,m),〇85 (1H,m),〇65 -0.62 (2H, m), 0.34 (1H, m). This example was isolated by palm chromatography to give the enantiomers 143A and 143B, which have the same spectral data. Example 14 4 Cyclopropyl (4-(ethylamino)-2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-tris. sitting_ι_yl)phenylamino) -8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5Ημ) ketone

To a solution of the preparation AE(R) (0.30 g, 0.67 mmol) in dioxet, was added diisopropylethylamine (0.17 g, 1.35 mmol) at -10 °C followed by cyclopropyl chloride (〇_084 g, 0.81 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water &lt The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) -methyl-1H-1,2,4-triazol-l-yl)phenylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H )-based ketone (0.14 g, 41%). LC-MS (M+H)+ = 513.4. NMR (400 MHz, CDC13(5): δ ppm 7.94 (2Η, m), 7.32-7.25 (4H, m), 7.13 (3H, m), 4.96 (1H, m), 4.22 (1H, m), 4.13 - 149653.doc -506- 201107311 4.04 (2H, m),3·93 (1H,m), 3.63 (2H,m)' 2.39 (3H, s), 1.35 (3H, t, J=7.2 Hz), 1.26 (1H, m), 0.87 (1H, m), 〇.66 (2H, m), 0.3 8 (1H, m). This example is isolated by palm chromatography to give the enantiomer l44A. And 144B 'both have the same spectral data. Example 14 5 N4 -ethyl_N2-(3-fluoro-4-(3-methyl-1H-1,2,4-tri. sit-1-yl) Phenyl)_ 8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro 0-bite [4,3-d] mouth bite-2 4-diamine

To the solution of the preparation AEP (0.20 g, 0.37 mmol) in THF was added 曱 side-DMS (0.061 g, 0.814 mmol, 2 Μ 喊 solution) at - 〇 °C. The reaction mixture was heated at 55 ° C for 18 hours. The reaction mixture was quenched with decyl alcohol and the solvent was evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) 2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidine-2,4-diamine (0.025 g, 14%). LC-MS (M+H)+=527.2. 4 NMR (400 MHz, DMSO-M): δ.ρρηι 9.32 (1 Η, s)5 8.67 (1H, s), 8.03 (1H, m), 7.41-7.38 (2H, m), 149653.doc -507· 201107311 7.27-7.18 (5H, m), 6.83 (1H, m), 3.97 (1H, m), 3.73 (1H, m), 3.57 (1H, m), 3.45 (2H, m), 3.37 (2H, m), 3.18 (1H, m), 2.97 (1H, m), 2.33 (3H·, s), 1.23 (3H, t, “7=7.2 Hz). Example 14 6 N4-Ethyl-N2-(3-Den-4-(5-methyltris-l-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoro Ethyl)-5,6,7,8-tetrahydroindene bite [4,3-(^]0-bite-2,4-diamine

To a solution of the preparation AEq (0.22 g, 0.40 mmol) in THF was added bromo-bromo-DMS (0.068 g, 0.89 mmol, 2 EtOAc ether). The reaction mixture was heated at 55 ° C for 18 hours. The reaction mixture was quenched with decyl alcohol, and the solvent was evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) ,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4 , 3-d]pyrimidine·2,4-diamine (0.030 g, 15%). LC-MS (Μ+Η)+=527·2. 4 NMR (400 MHz, DMSO-m): δ ppm 9.37 (1H, s), 8.04 (1H, s), 8.00 (1H, m), 7.42 ( 1H, m), 7.30-7.20 (6H, m), 6.84 (1H, m), 3.98 (1H, m), 3.73 (1H, m), 3.69 (1H, m)5 3.57-3.48 (4H, m) , 3.23 (1H, m), 2.99 (1H, m), 149653.doc - 508- 201107311 2.26 (3H·, s), 1.23 (3H, t, “7=7.2 Hz). Example 147 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-6-(methylsulfonyl)-8-benzene Base-5,6, 7,8-tetrahydrogen. Bis-pyrene[4,3-d]pyrimidine-

2,4-diamine

The preparation AEC was converted to N2-(4-(4-chloro-1H-imidazo-bu)-3-methoxyphenyl)-N4,N4 using the procedure of Preparation AEd, Preparation AEj, and Example 134. - Dimercapto-6-(nonylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine. ZC-MS (M-H)+ = 552.2. 4 NMR

(400 MHz, OMSO-d6): δ ppm 9.27 (1Η, s), 7.91 (1H, s), 7.73 (1H, m), 7.42 (1H, m), 7.31 (2H, m), 7.25-7.10 ( 5H, m), 4.46 (1H, m), 4.30-4.24 (2H, m), 3.83 (1H, m), 3.53 (3H, s), 3.28 (1H, m), 3.13 (6H, s), 3.09 (3H, s). Example 148 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,6-dimethyl-8-phenyl-5,6,7,8 -tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

149653.doc - 509-201107311 Preparation of A (〇.26 g, 1.2 mmol) with argon at room temperature, preparation Afa (0.35 g '1.2 mmol), Na2CO3 (0.25 g, 2.4 mmol) and xantphos (0.69 g, 1.2 mmol) of the solution in dioxane/water (9:1) for 1 hour. Pd(dba)3 (0.55 g, 0.6 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at i 10 ° C for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with a brine solution (25 mL) and dried over anhydrous NajEtOAc, and evaporated under reduced pressure to give a crude compound. Purification of the crude compound by preparative HPLC (methanol containing 0.5% aqueous acetic acid) afforded N2-(4-(4-H-1H-imidazol-1-yl)-3-decyloxy Base)_N4,6-diamidino-8-phenyl_5,6,7,8-tetrahydro 0 is more dense than [4,3-d]°. -2,4-Diamine (〇.1〇 g, 18%). LC-MS (M+H)+ = 476.2.丨H NMR (400 MHz, DMSO-dosed): δ ppm 9.05 (1H, s), 8.05 (1H, s), 7.71 (1H, s), 7.40 (1H, s), 7.27-7.17 (5H, m) , 7-15-7.06 (2H, m)s 6.76 (1H, m), 3.94 (lH, m), 3.50 (3H, s), 3.39 (1H, m)5 3.18 (1H, m), 2.95 (3H , ds J=4.4 Hz), 2.51 (1H, m), 2.49 (1H, m), 2.12 (3H, s). This example was isolated by palm chromatography to give enantiomers 148 and 148B, both having the same spectral data. Example 14 9 N2-(3-Fluoro-4-(3-methyl-1H-1,2,4-triazole-[-yl)phenyl)_N4 6 dimethyl, 8-phenyl-5,6 ,7,8-tetrahydropyrido[4,3-d] sneezing _2 4-diamine 149653.doc •510- 201107311

Preparative B (0.21 g, 1.1 mmol), preparation AFa (0.35 g '1.2 mm〇l), Na2CO3 (0.25 g, 2.4 mmol) and argon were purged at room temperature.

Xantphos (0.70 g, l.i mm〇l) in dioxane / water (9:1) solution, time. Pd(dba)3 (〇.55 g, 0.6 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at 110X: for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL x 3). The combined organic layer was washed with brine (25 mL) and dried over anhydrous Naj. Purification of the crude compound by preparative HPLC (purified with 0.5% aqueous EtOAc in EtOAc) afforded </ </ RTI> </ RTI> </ RTI> (3-fluoro-4·(3-methyl-1H-1,2,4- Triazol-1-yl)phenyl)-indole 4,6-dimethyl·8-phenyl_5 6,7,8•tetrahydropyridyl[4,3-d]biting-2,4- Diamine (〇.2 g '38%). LC-MS (Μ+Η)+= 445.2. H NMR (400 ΜΗζ, DMSO-state: δ ppm 9.33 (1Η, s), 8.67 (1H, s), 8.05 (1H, m), 7.41 (2H, m), 7.3-7.20 (5H, m), 6.84 (1H, m), 3.96 (1H, m), 3.42 (1H, m), 3.25 (1H, m), 2.94 (3H,d,J=4.4 Hz), 2.92 (1H, m), 2.71 (1H, m), 2.51 (3H, s), 2.40 (3H, s). Example 150 N2-(3-Fluoro-4-(5-methyl-1Η-1,2,4·triazole-i-yl)benzene基)·Ν46_ dimethyl I49653.doc -511· 201107311 -8-phenyl-5,6,7,8-tetrahydrogen ratio bite [4,3-d]. 密定定-2,4- Diamine

Prepare C (0.23 g, 1.2 mmol), preparation AFA (0.35 g, 1.2 mmol), Na2CO3 (0.25 g, 2.4 mmol) and xantphos (0.69 g, 1.2 mmol) in argon at room temperature . When the solution in the smoldering/water (9:1) is ^. Pd(dba)3 (〇.55 g, 0.6 mmol) was added to the reaction mixture and the resulting solution was again purged with nitrogen for 1 hour. The reaction mass was heated at 1 l ° ° C for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na.sub. N2-(3-Fluoro-4-(5-fluorenyl-1H-' '- meth) base)-N 4,6-didecyl-8-phenyl-5-6 was obtained as an off-white solid. 7,8-tetrahydro 0-pyrido[4,3-d]pyrimidine-2,4-diamine (0.08 g, 15%) clC-MS (Μ+Η)+= 445.2. η NMR (400 MHz, DMSO-i/6): δ ppm 9·38 (1Η, s), 8·〇6 (1H, m), 8 00 (1H, s), 7 44 (1H, m), 7 3〇7 23 (5H, m)s 7·18 (1H, m), 6.84 (1H, m), 3.95 (1H, m), 3.40 (1H, m), 3.22 (1H, m), 2.93 ( 3H, d, *7 = 4.4 Hz), 2.90 (1H, m), 2.86 (1H, m), 2.36 (3H, s), 2.26 (3H, s). Example 151 149653.doc -512· 201107311 -(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_N4-ethyl-6.methyl-8-phenyl -5,^8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine

Prepare A (〇.26 g, 1.19 mmol) with argon at room temperature

A solution of AFb (0.4 g ' 1.32 mmol), Na2CO3 (0.28 g, 2.64 mmol) and xantphos (0.76 g, 1.32 mmol) in dioxane/water (9:1) for 1 hour. Pd(dba)3 (0.60 g, 0.66 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated under uo〇c for 24 hours. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (50 mL &lt;&lt; 2). The combined organic layer was dried with anhydrous NajO 4 and dried under reduced pressure to give a crude compound. Purification of the crude compound by preparative HPLC (methanol) eluting with EtOAc (EtOAc: EtOAc) _N4-ethyl-6-mercapto-8-phenyl-5,6,7,8-tetrahydro 0-pyrido[4,3-d]pyrimidine-2,4-diamine (0.15 g, 24% ). LC-MS (M+H)+ = 490.2. NMR (400 MHz, DMSO-m): δ ppm 9.01 (1H, s), 7.97 (1HS s), 7.71 (1H, s), 7.40 (1H, s), 7.39-7.20 (5H, m), 7.18- 7.07 (2H,m), 6.70 (1H,m),3.95 (1H,m),3_57 (3H, s), 3.56 (2H, m), 3.47 (1H, m), 3.18 (1H, m), 2.85 (1H, m), 2.59 (1H, m), 2.34 (3H, s), 1.22 (3H, t, /=7.2 Hz). I49653.doc • 513-201107311 The separation of the racemic mixture by palm chromatography gave the enantiomeric examples 15 1A and 15 1B ' both having the same spectral data. Example 152 N4-CS-N2-(3~gJ-4.(3. f S-1H-1,2,4-^^6-methyl-8-stupyl-5,6,7,8-four Hydropyrido[4,3-d] spray bite _2i4-diamine

Prepare B (0-12 g, 〇59 mm〇1), preparation AFb (0.20 g '0.66 mmol), Na2C03 ((M4 g, 1.32 mmol) and Xantph〇S (0.38 g) with argon at room temperature. , 0.66 mmol) solution in dioxane / water (9:1) for 1 hour. Add Pd(dba)3 (0.30 g, 0.33 mmol) to the reaction mixture and wash the resulting solution for 1 hour with mouse gas. The reaction mass was heated for 24 hours at 1 Torr. The reaction was transferred over a celite (c.) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with aq. (3 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous NaCI and evaporated under reduced pressure to give a crude compound by preparative HPLC (methanol with 0.5% aqueous ammonium acetate) To purify the crude compound to give N4-ethyl-N2-(3-fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-6 as an off-white solid _Mercapto-8_phenyl_ 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (〇·〇3 g, 11%). LC-MS (M+H)+=459.2. 4 NMR (400 MHz, DMSO-m): δ ppm 9.31 (1H, s), 8.67 (1H , s), 8.04 (1H, m), 7.40 (2H, m), 149653.doc -514- 201107311 7·29-7·17 (5H,m), 6.81 (1H,m),3.95 (1H,m ), 3.48 (2H, m), 3·43 (1H, m), 3.21 (ih, m), 2.91 (1H, m), 2.68 (1H, m), 2.38 (3H, s), 2.33 (3H, s), 1.23 (3H, t, 7=7.2 Hz) ° Example 153 N4-ethyl-N2-(3-fluoro-4-(5-mercaptotriazol-1-yl)phenyl>_ 6-A -8-phenyl-5,6,7,8-tetra-I pyrido[4,3-d]pyrimidine-2,4-diamine

Prepare c (〇15 g, 〇82 mm〇1), preparation AFb (0.25 g '0.82 mmol), Na2CO3 (0.17 g, 1.6 mmol) and xantphos (0.42 g, 0.82) with argon at room temperature. Mm〇i) A solution of dioxane/water (9:1) for 1 hour. Pd(dba)3 (0.37 g, ο. &quot; 111111〇1) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at u 〇 0 C for 24 hours. The reaction was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL &gt;&lt;3). The combined organic layers were washed with a brine solution (25 mL) dried over anhydrous Nad.sub.4 and evaporated under reduced pressure to afford crude compound. The crude compound was purified by preparative EtOAc (EtOAc:EtOAc:EtOAc -1,2,4-tris.-1-yl)phenyl)-6-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 2,4-Diamine (0.06 g, 17%). LC-MS (M+H)+=459.2. 4 NMR (400 MHz, CDC13): δ ppm 7.93 149653.doc •515·201107311 (1H,s),7.84 (1H,m),7.34-7.27 (5H, m), 7.26-2.20 (2H, m)s 7.05 (1H, m), 4.65 (1H, m), 4.11 (1H, m), 3.61-3.54 (2H, m), 3.39 (2H, m), 3.07 (1H, m), 2.81 (1H, m), 2,51 (3H, s), 2.37 (3H, s), 1.34 (3H, t, *7 = 7.2 Hz). Example 154 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-indole 4-methyl, 6-(methylsulfonate Indenyl)-5,6,7,8-tetrahydropyrido[4,3-technical]pyrimidine-2,4-diamine

Add diisopropylethylamine (0.043 g, 0.33 mmol) to a solution of the preparation AGk (0.08 g, 0.167 mmol) in dioxane at 〇 ° C. Then add decane sulfonium (0.029 g) , 0.167 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with dioxane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Phenyl)-8-(4-fluorophenyl)-N4-indolyl-6-(nonylsulfonyl)-5,6,7,8-tetrahydroacridino[4,3-d]pyrimidine -2,4-Diamine (0_02 g, 23%). LC-MS (M+H)+ = 558.0. !H NMR (400 MHz, DMSO-^&lt;5): δ ppm 9.21 (1Η, s), 8.0 (1H, s), 7.73 (1H, s), 7.42 (1H, s), 7.27-7.23 (2H , m), 7.16-7.12 (4H,m),7.05 (1H,m), 4.20 (1H,m),4.12 (1H,m), 149653.doc • 516- 201107311 4.05 (1H, m), 3.56 ( 3H, s), 3.51-3.47 (2H; m)} 2.97 (3H, d X0 Hz), 2.91 (3H, S). This example was isolated by palm chromatography to give the same spectral data for both enantiomers 154 and 1 54B'. Example 15 5 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_N4_ethyl(4-fluorophenyl)-6-(methylsulfonyl)_5 , 6, 7, 8 - four. More than cough and [4,3-d]. Densification, 1A-diamine

Triethylamine (〇_037 g, 0.36 mmol) was added to a solution of the preparation AG1 (0.09 g, 0.018 mmol) in dichloromethane at 〇 ° C, followed by the addition of methane sulfonium chloride (0.021 g, hydrazine) _182 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Phenyl)-N4-ethyl-8-(4-fluorophenyl)-6-(indolyl)-5,6,7,8-tetrapyridinium[4,3-d]pyrimidine- 2,4-Diamine (〇.〇4 g, 39%). LC-MS (MH)+=572.0. 4 NMR (400 MHz, DMSO-^^): δ ppm 9.18 (1H, s), 7.95 (1H, s), 7.73 (1H, s), 7.42 (1H, s ), 7.27-7.23 (2H, m), 7.17-7.12 (4H, m), 6.99 (1H, m), 4.24 (1H, d, /=14.0 Hz), 4.12 (1H, 149653.doc -517- 201107311 s), 3.55-3.47 (4H, m), 4.04 (1H, d, "7=14.0 Hz", 3.56 (3H, m), 2.92 (3H, s), 1.22 (3H, t, &gt;/=7.2 Hz). This example was isolated by palm chromatography to give the same spectral data for both enantiomers MM and 15 5B '. Example 15 6

8-(4-Fluorophenyl)_6-(Gas-toile) 5-,6,7,8-tetrahydro-v-pyridyl[43_d] „Milent-2,4-diamine

Diisopropylethylamine (0.168 g, 0.29 mmol) was added to a solution of the preparation AGm (0.30 g, 0.649 mmol) in hexanes at 0 C, followed by the addition of sulphuric acid (0.07 g, 0.649) Mm). The anti-mad mixture was mixed for 1 hour at room temperature. The reaction mixture was diluted with dioxane, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative H.sub.sub.sub.sub.sub.sub.sub. 1H-1,2,4-triazole-indole-yl)phenyl)-6-(anthracenyl)-8-phenyl-5,6,7,8-tetra-argon. Bis-[4,3-(;1]pyrimidine-amine (0.250 g '71%). LC-MS (M+H) = 54 1.2. 4 NMR (400 MHz, DMSO-cM): δ ppm 9.45 (1H, s), 8.69 (1H s) 8.01 (lH, m), 7.47-7.40 (2H, m), 7.39-7.26 (2H, m), 715_ 7.07 (3H, m), 4.20 (1H, m ), 4.2-4.06 (2H, m), 3.63 (1H, 149653.doc -518- 201107311 ^)&gt; 3.54-3.48 (3H, m), 2.94 (3H, s), 2.34 (3H, s), 1.22 (3H, t, · Ζ = 7. 2 Hz). This example was isolated by palm chromatography to give the enantiomers 156 and 150B, both having the same spectral data. Example 157 Ν 4-B Base-Ν2-(3-fluoro_4_(5-methyltriazole-:[-yl)phenyl)_6_(methylsulfonyl)-8-(4-1-Zhuliang)-5,6, 7, 8-tetrahydroacridine [4,kd] shout

To a solution of the preparation AGn (0.25 g, 0.540 mmol) in methylene chloride was added diisopropylethylamine (0139 g, ι·080 mmol) under 〇C, followed by the addition of bismuth and sinter. 06 g, 0.540 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water &lt The crude compound was purified by preparative EtOAc (EtOAc EtOAc EtOAc) 1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)_8·(4-fluorophenyl)_5,6,7,8-tetrahydro-pyridyl[4 , 3-d] pyrimidine-2,4-diamine (〇·ΐ9 g, 73%). LC-MS (MH)+=541.2. 4 NMR (400 MHz, DMSO-m): δ </ RTI> </ RTI> 9.48 (1H, s), 8.01 (in, m), 7.97 (1H, 1H), 7.43 (1H, m) , 7.34-7.27 (3H, m), 7.15-7.11 (2H, m), 7.05 (1H, m), 4.23-4.07 149653.doc -519· 201107311 (3H,m),3.63 (1H, m), 3.55 -3.48 (3H, m), 2.94 (3H, s), 2·28 (3H, s), 1.24 (3H, t, J=7.2 Hz) 分离 Separate this example by palm chromatography to get ' The two isomers i57A and 15?B' have the same spectral data. Example 15 8 Ν2-(4·(4_Chloro·ιη~M..-1-yl)methoxymethoxyphenyl)-N4,6-diethyl-8~(4-fluorophenyl)-N4 -methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-

Triethylamine (0.004 g, 0.039 mmol) was added to a solution of EtOAc (EtOAc (EtOAc). At 80. (The reaction mixture was heated under reduced pressure for 18 hours. The solvent was removed under reduced pressure and the residue was diluted with water. ethyl acetate (10 mL×3) was used to extract the aqueous layer. The combined organic layer was washed with water and dried over anhydrous Na? Evaporation to give the crude compound. EtOAc (m.) 1-yl)-3-methoxyphenyl)-N4,6-diethyl_8-(4-fluorophenyl)_N4_fluorenyl_5,6,7,8-tetrahydropyrido[4 ,3-d] 'pyridine 2,4_ diamine (〇〇4 g, 40%). LC-MS (M+H)+=536.2 〇&gt;H NMR (4〇〇MHz, fm~d4): δ ppm 7.80 (1Η, s), 7.67 (1H, s), 7.26-7.22 (3H, m), 7.13 (1H, m), 149653.doc • 520- 201107311

7 〇7-7.〇〇(2H,m),6·98 (1H,m), 4.23 (1H,m),3.75 (1H H3 Μ (6H,^ 3·33 (1H, called, 3_28 (3H) , S), 2.69 134 (3H m), 丨 3 () (3h Example 159 N-(4-(4-chloro-1H_imisinyl)·3•methoxyphenyl b 4_(u-two Heterocyclic dimeric small base) _8_(4_fluorophenyl)_6m6,78_tetrahydrogen.

[4,3-d] «Mole - 2-amine

Add K2C〇3 (〇.(m, 0.083 咖.丨) to the solution of the preparation AGp (〇.〇3 g, 〇〇55 mm〇丨) in C- at room temperature, followed by the addition of armor. (〇·〇12 g, 0.083 mm 〇i). The reaction mixture was stirred at room temperature for 2 hr. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (1 〇mL×3). Wash the combined organic layer, without water

The NajO4 was dried and evaporated under reduced pressure to give a crude compound. The crude compound was purified by preparative HPLC (hexanes containing 1% aqueous ammonium acetate) to give N-(4-(4-H-1H-imidazol-1-yl)-3-methoxyphenyl ) 4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetra-argon [4,3-d]pyrimidin-2-amine (0.007 g, 24%). LC-MS (Μ+Η)+=556·2. H NMR (400 MHz, DMSO-c/(5): δ ppm 10.50 (1 Η, s), 9.56 (1H, s), 7.75 (1H, s), 7.43 (1H, s), 7.33-7.30 (2H, (m), 7.25- , 4·43 (3H, m), 3.88 (iH, m), 3.51 (3H, s), 2.97 (3H, s). Example 160 N-(4-(4-Ga-1H-imidazole-U group) _3_foxyphenyl)_4_(3&gt;3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-56,7,8-tetrahydro. Specific [4,3-d]pyrimidin-2-amine

Add Cs2C03 (0_036 g, 0.U mm〇1) to the solution of the preparation AGp (0.040 g, 〇〇73 mm〇1) in acetone, followed by the addition of methanesulfonate (0.012 g'0.U mm〇) l). The reaction mixture was allowed to stand at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (1 mL) &lt;3. The combined organic layers were washed with EtOAcq. The crude compound was purified by preparative EtOAc (EtOAc:EtOAc) NMR (400 MHz, DMSO-m): δ ppm 9.47 (1H, s), 7.85 (1H, s), 7.74 (1H, s), 7.43 (1H, s), 7.30-7.26 (2H, m), 7.18 -7.09 (4H, m), 4.77-4.70 (4H, m), 4.36 (1H, m), 4.24 (2H, m), 3·66 (1H, m), 3.56 (3H, s), 3_44 (1H , m), 3_0 (3H, s). 149653.doc -522-201107311 This example was isolated by palm chromatography to give the same spectral data for both enantiomers 160A and 160B'. Example 161 N2-(4~(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-'^4-A Base_5,6,7,8-tetrahydropyrido[4,3-(11]pyrimidine-2,4~

This compound is similar to the preparation AGo (see above). Example 162 N-(4-(4-Gas-1H-imidazol-1-yl)-3-methoxyphenyl)_4-(3 3 -difluoroazetidin-1-yl)-8- (4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3_d]a^

Bite-2-amine F F

This compound is similar to the preparation AGp (see above). This example was isolated by palm chromatography to give individual enantiomers 162 and 162B, each having the same spectral data. 149653.doc - 523 - 201107311 Example 163 N2-(4-(4-Ga-1H-imidazol-1-yl)-3- methoxyphenyl)-8-(4-fluorophenyl)-indole 4,6 -Dimethyl-5,6,7,8-tetrahydropyrido[4,3-(11]pyrimidine-2,4-diamine

The preparation hydrazine (0.109 g, 0.49 mmol), the preparation AHa (0.15 g, 0.49 mmol), Na2C03 (0.103 g, 0.98 mmol) and xantphos (0.283 g, 0. A solution of methane/water (9:1) for 1 hour. Pd(dba)3 (0.253 g, 0.24 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at 11 ° C for 24 hours. The reaction mass was filtered through a pad of Celite (EtOAc) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL x 3). The combined organic layers were washed with EtOAc (EtOAc m. Purification of the crude compound by preparative HPLC (methanol containing 0.5% aqueous ammonium acetate) afforded N2-(4-(4-chloro-1H- miso-1-yl)-3-indole as an off-white solid Phenyl)-8-(4-fluorophenyl)-N4,6-diamidino-5,6,7,8-tetrahydropyrido[4,3-(1]pyrimidine-2,4-di Amine (〇.〇35 吕, 14%) LC-MS (Μ+Η).=494·2. NMR (400 MHz, DMSO-m): δ ppm 9.07 (1H, s), 8.32 (1H, s ), 8.05 (1H, s), 7.72 (1H, s), 7.26 (2H, m), 7.14-7.05 (4H, m), 6.77 (1H, m), 3.96 (1H, 149653.doc •524· 201107311 m), 3.94 (3H, s), 3.42 (1HS m), 3.11 (1H, m)5 2.92 (3H, ds •/=4.4 Hz), 2.82 (1H, m), 2.58 (1H, m), 2.33 (3H, s) Separation of the racemic mixture by palm chromatography afforded enantiomers Examples 163 and 1638, both having the same spectral data. Example 16 4 N2-(4-(4 -chloro-1H-imidazolyl)_3_methoxyphenyl)_N4ethyl-8_(4-fluorophenyl)-6-fyl-5,6,7,8-tetrahydropyrido[43_d]pyrimidine _2,4-diamine

Prepare A (〇146 g, 〇65〇丨), preparation AHb (0.210 g '0.650 mmol), Na2CO3 (; 0.139 g, 1.30 _〇l) and Xantph〇S (with argon blowing) under a dish. 0.378 g, 0·650 mm 〇 1) solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (〇.338 g, 0.327 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for a few hours. The reaction mass was heated for 24 hours under 丨1〇&gt;c. The reaction mass was filtered through a pad of Celite® and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with aq. EtOAc (EtOAc EtOAc (EtOAc) , N2_(4_(4_ 149653.doc -525- 201107311 gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-8-(4-fluorol) was obtained as an off-white solid Phenyl)-6-methyl-5,6,7,8-tetrahydroindole and [4,3-(1]pyrimidine-2,4-diamine (0,022 L, 22%) = LC-MS ( M+H)+=508.0 0 ]H NMR (400 MHz, DMSO-d6): δ ppm 9.07 (1H, s), 7.97 (1H, s), 7.73 (1H, s), 7.41 (1H, s), 7.29-7.23 (2H, m), 7.15-7.05 (4H, m), 6.73 (1H, m), 3.96 (1H, m), 3.56 (3H, s), 3.49-3.40 (3H, m), 3.13 ( 1H, m), 2.83 (1H, m), 2.62 (1H, m) 2.34 (3H, s), 1.21 (3H, t, /=7.2 Hz). Separation of the racemic mixture by palm chromatography Enantiomers Examples 1 64A and 1 64B were obtained, both having the same spectral data. Example 165 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl )-N4-ethyl-8-(4-fluorophenyl)-_&gt;6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-(1]pyrimidine Acridine - 2,4-^ January

The preparation Α(〇·ΐ8 g, 〇_8〇mmol), preparation AHc (0.30 g, 0.89 mmol), Na2CO3 (0.190 g, 1.79 mmol) and xantphos (0.519) were purged with a rat under a dish. g, 0.89 mmol) in dioxane / water (9:1) for 1 hour. Pd(dba)3 (〇 465 g, 〇 44〇 mm〇1) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. At 1丨〇. Underarm heating 149653.doc - 526- 201107311

The reaction was allowed to stand for 24 hours. The reaction mixture was filtered through a pad of Celite (CeUte, filtered and washed with ethyl acetate). The mixture was evaporated to dryness under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (20 mL×3). The organic layer was dried with EtOAc (EtOAc m. 2_(4_(4_Chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)·Ν4-ethyl·8·(4-fluorophenyl)·Ν4,6_ monomethyl-5, 6,7,8-tetrahydroindole ratio bite [4,3-&lt;1] 〇密口定-2,4-diamine (〇.13 diameter,. ISo/o^LC-MSCM+HrsSlZ.t ^hNMROOOMHz'DMSO- d6)·. δ ppm 9.13 (1H, s), 7.86 (1H, s), 7.73 (1H, s), 7.42 (1H, s), 7.24 (2H, m), 7.15-7.07 ( 4H, m), 4.13 (1H, m), 3.55 (3H, s), 3.47-3.41 (4H, m)5 3.04 (3H, s), 2.99 (1H, m), 2.48 (1H, m), 2.34 (3H, s), I·23 (3H, t, /= 7.2 Hz). The racemic mixture was separated by palm chromatography to give enantiomers 165A and 165B, both of which have the same Spectral data. Example 166 N 2-(4-(4-Gas-1H-Mircester small) Winter Methoxyphenyl)-N4-Ethyl-8-(4-fluorophenyl)_]^4-Gas _56 7, 8-tetrahydrogen 0 ratio bite [3,4-Phase ° bite-2,4-diamine

149653.doc -527- 201107311 This example is the same compound as the preparation All (see above). Example 167 Ν_(4·(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrole Acridine-buyl)-?-^-methoxybenzyl)_5&gt;6J,8-tetrazine ratio bite [3,4-d] °

Preparative A (0.190 g, 0.851 mmol), preparation Ald (0.40 g '0.851 mmol), Na2C03 (〇.180 g, ΐ·7〇mmol) and xantphos (0.491 g, were purged with argon at room temperature. 0.851 mmol) solution in dioxane / water (9:1) for 1 hour. Pd(dba)3 (0.440 g, 0.425 mmol) was added to the reaction mixture and the resulting solution was again purged with argon for 1 hour. The reaction mass was heated at 丨丨Ot for 24 hours. The reaction mixture was filtered over celite (CeHte®) and washed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (25 mL &gt;&lt;3). The combined organic layers were washed with brine (2 mL) and dried over anhydrous NaHEtOAc. The crude compound was purified by column chromatography (6 〇 〇 〇 ) ) , , , , , 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油 石油沭(1)-(a)-gas-indolizyl-1_yl)-3-methoxyphenyl)_8_(4-fluorophenyl)_4_((8)_3_范吼吼 bit-1-yl)-7-(4 -Methoxybenzyl)_5,6,7,8-tetrahydropyridin [3,4 149653.doc •528· 201107311 pyridine-2-amine (0.40 g, 88%, crude). LC_MS (M+H)+=658 2. NMR (400 ΜΗζ, DMSO-m): δ ppm 8.95 (1 Η, S), 7.75 (1 Η s), 7.74 (1H, s), 7.54 (2H, m), 7.43 (1H, s), 7.29 (lHj m )^ 7.22-7.14 (5H,m), 6.86 (2H,m), 5.34 (1H,m), 4.38 (iH, s), 4.03 (1H, m), 4.0 (3H, m), 3.72 (6H, s), 3.51 (lH, m),

3-33 (1H, m), 2.95 (2H, m)5 2.51 (1H, m), 2.25-2.01 (3H m). φ Separation of the mixture of diastereomers by palm chromatography gave two diastereomer examples 167A and 167B. Example 168 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)·Ν4_ethyl_8 (4-fluorophenyl)-7-(methionite) Stuffed base) _5,6,7,8-tetrahydrogen. More than bite [3,4-d]. Bite 2,4-diamine

Diisopropylethylamine (0.041 g, 0.243 mmol) was added to a solution of the preparation AIK (0.06 g, 0.121 mmol) in a gas chamber at -10 °C, followed by the addition of a scutellite (0.013 g, 0.121 mmol). The reaction mixture was allowed to stand at room temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water and evaporated evaporated The crude compound was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) Phenyl)_n4_ 149653.doc •529· 201107311 Ethyl-8-(4-fluorophenyl)-7-(nonylsulfonyl)_5,6,7,8-tetrahydro. Bis-pyrene [3 4 d]» bite 2,4-diamine (0.020 g '29 ° /.). LC-MS (M+H)+ = 572 2. !H NMR (400 MHz, DMSO-i/6): δ ppm 9.23 (1H, s), 7 9? (1H, s), 7.74 (1H, s), 7.43 (1H, s), 7.35 (2H, m)5 7.23-7.l2 (4H,m),7.0 (1H,m),5.57 (1H,s),3.85 (1H,m),3.79 (3H s),3.54 (2H,m),3.18 ( 1H,m),2.88 (3H,s),2.65 (2H,m)' 1·24 (3H,t,*/=7·2 Hz) 分离 separation of the racemic mixture by palm chromatography Two enantiomeric examples 168A and 168B were obtained. Example 169 N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)_N4,7-diethyl_

Add diisopropylethylamine (〇1〇4 g '〇8〇6 mm〇1) to the solution of the preparation AIK (0.20 g, 0.405 mmol) in dioxane at -10 ° C, followed by the addition of iodine Ethane (0·31 g '0.231 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with methylene methane, washed with water, and evaporated to dryness. The crude compound was purified by preparative EtOAc (EtOAc (EtOAc:EtOAc) -N4,7-diethyl-8-(4-fluorophenyl)_5,6,7,8-tetrahydropyrido[3,4_£1]pyrimidine_2,4-diamine 149653.doc 201107311 ( 0.110 g, 62 〇 / 〇). LC-MS (M+H)+ = 522.2. NMR (400 MHz, DMSO-〇?(5): δ ppm 8.90 (1H, s), 7.70 (1H, s), 7 73 (1H, s), 7.42 (1H, s), 7.28 (2H, m) , 7.17 (4H, m), 6.78 (1H, m), 4.39 (1H, s), 3.65 (3H, s), 3.48 (2H, m), 3.13 (2H, m), 3.08 (1H, m), 2.51 (1H, m), 2.39 (2H, m), 1.22-1.19 (6H, m). The separation of the racemic mixture by chromatography afforded the two enantiomers 169A and 169B. Example 170 2_(4_(4-Chloro-1H-imidazol-1-yl)-3.methoxyphenylamino)_4_(ethylaminofluorophenyl)-5,6-dihydro-sigma ratio bite [ 3,4-d] 〇密唆-7(8H)-formic acid

Triethylamine (0.019 g, 0.20 mm 〇i) was added to a solution of the preparative material AIk (0.10 g, 〇. 20 mmol) in dioxane, followed by the addition of decyl phthalate (0.18 g, 0.20 mmol) ). The reaction mixture was stirred at room temperature for J hours. The reaction mixture was diluted with a methylene chloride, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative HPLC (EtOAc EtOAc (EtOAc) elute )_4_(ethylamino)_8_(4-fluorophenyl)_5,6-dihydro 0 is 0 and [3,4_d]pyrimidine. Ding·7(8Η) decyl carboxylate 149653.doc 531- 201107311 (0.080 g, 76%). LC-MS (Μ+Η)+=552·2. 4 NMR (400 MHz, DMSO-g?^): δ ppm 9.22 (1H, s), 7.96 (1H, s), 7.74 (1H, s), 7.48 (1H, s), 7.33 (2H, m), 7.20-7.13 (4H, m), 6.98 (1H, m), 4.06 (1H, s), 3.82 (1H, m), 3.75 (3H, s) , 3.68 (3H, s), 3.56 (2H, m), 3.02 (1H, m), 2.33 (2H, m), 1.21 (3H, t, •/=7.2 Hz) » by palmography The racemic mixture was isolated to give two enantiomers, examples 170A and 170B. Example 1Ί1 1-(2-(4-(4-Chloro-1H-imidazol-1-yl)-3·f-oxyphenylamino)-4-(ethylamino)-8-(4-1phenyl) -5,6-dihydrogen ratio bite [3,4-€1] mouth bite-7 (81{)-base)

Ethyl ketone CI

Add triethylamine (0.012 g, 〇126 Gu〇1) to a solution of the preparation AIK (0.052 g, 〇.1〇1 mm〇1) K dichloromethane at -10 °C, followed by addition Ethylene gas (0.007 g, 〇.〇1 mm〇l). The reaction mixture was diluted with chlorohexane at rt. The crude compound was purified by preparative HpLC (yield: EtOAc (1% EtOAc) EtOAc (EtOAc) Base) 8 (4fluorophenyl)_5,6-dihydron-pyrido[3,4 d]pyrimidinyl)ethanone 149653.doc - 532-201107311 (0.040 g, 72%). LC-MS (M+H)+=536.2. 4 NMR (400 MHz, DMSO-c/5): δ ppm 9.25 (1H, s), 8.0 (1H, s), 7.75 (1H, s), 7.43 ( 1H, s), 7.32 (2H, m), 7.21-7.14 (4H, m), 6.99 (1H, m), 6.36 (1H, sb), 3.95 (1H, m), 3.90 (2H, m), 3.57 (3H, s), 3.49 (1H, m), 3.20 (1H, m), 2.34 (1H, m), 2.12 (3H, s), 1.22 (3H, t, *7 = 7.2 Hz). Example 1Ί2

N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7- (Methanesulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

To a solution of the preparation AI1 (0.070 g, 0.138 mmol) in dioxin, diisopropylethylamine (0.047 g, 0.276 mmol) was added at -10 ° C, followed by the addition of a calcined helium (〇 ·〇15 g, 0·138 mmol). The reaction mixture was searched for 1 hour at room temperature. The reaction mixture was diluted with methylene chloride, washed with water and evaporated under reduced pressure to give crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Stupid N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7-(nonylsulfonyl)_5,6,7,8-tetrahydropyridinium [3,4-d Pyrimidine-2,4-diamine (0.030 g, 37%). LC-MS (M+H)+= 586.2. NMR (400 MHz, DMSO-m): δ ppm 9.26 149653.doc •533 - 201107311 ( 1H, s), 7.80 (1H, s), 7.74 (1H, s), 7.43 (1H, s), 7.34 (2H m), 7.32-7.16 (4H, m), 5.65 (1H, s), 3.55 ( 1H,m),3 S3 (3H,s),3.51 (2H,m)' 3.18 (1H,m),3.08 (3H,s),2.9i (3h s),2.67 (1H,m),1.22 ( 3H,m). Two enantiomeric example 172 and 1726 were obtained by separation of the racemic mixture by palm chromatography. Example 173 N-(4-(4-Ga-1H-imidazole-1) -yl)-3-methoxyphenyl)-8-(4-d-phenyl)- 4-((R)-3-fluoropyrrolidin-1-yl)-7-(methylsulfonyl)- 5,6,7,8-tetrahydropyridine. Dino[3,4-d]pyrimidin-2-amine

Add diisopropylethylamine (0.019 g, 0.148 mmol) to a solution of the preparation AIM (0.041 g, 〇.〇74 mmol) in dioxet at -1 〇C, followed by the addition of smoldering Gas (0.008 g, 0.074 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane, and washed with water and evaporated under reduced pressure to afford crude compound. The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Oxyphenyl)-8-(4-1phenyl)-4-((R)-3-1 0-pyridyl-buyl)-7-(sulfonyl)-5'6,7, 8-tetrahydropyrido[3,4_(1]pyrimidin-2-amine (〇.〇1〇§, 20%). 1^- 149653.doc -534 - 201107311 MS (M+H)+=616.0 〇 !H NMR (400 MHz, OUSO-d6): δ ppm 9.27 (1H, s), 7.84 (1H, s), 7.75 (1H, s), 7.43 (1H, s), 7.38 (2H, m), 7.22 -7.17 (4H, m), 5.50 (1H, s), 4.11 (1H, m), 4.04 (3H, m), 3.82 (1H, m), 3.51 (3H, s), 3.23 (2H, m), 3.05 (2H, m), 2.95 (3H, s), 2.23 (2H, m) ° Example 174

N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-4-(())-3-fluoropyrrolidine -1-yl)_7-(methylsulfonyl)-5&gt;6,7,8-tetrahydroacridino[3,4-d]pyrimidin-2-amine

To a solution of the preparation AIn (0.041 g, 0.074 mmol) in methylene chloride was added diisopropylethylamine (0.019 g, 0.148 mmol), then decanesulfonium chloride ( 0.008 g, 0.074 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water &lt The crude compound was purified by preparative EtOAc (EtOAc EtOAc (EtOAc) Phenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-7-(sulfonyl)-5,6,7,8 Tetrahydropyrido[3,4-d]pyrimidin-2-amine (0.012 g, 20.6%). LC-MS (M+H)+=616.0. 4 NMR (400 MHz, DMSO-Liu δ 149653.doc -535 · 201107311 ppm 9.25 (1H, s), 7.83 (1H, s), 7.74 (1H, s) , 7.42 (1H, s), 7.33 (2H, m), 7.22-7.12 (4H, m), 5.76 (1H, s), 5.57 (1H, m), 4.07 (1H, m), 3.99-3.90 (3H , m), 3.88 (1H, m), 3.54 (3H, s), 3.27 (1H, m), 3.11 (1H, m), 2.93 (3H, s), 2.85 (1H, m), 2.23 (2H, m). Example 17 5 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7 -methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

The preparation Aik and iododecane were combined in the same manner as in Example 169 to give N2-(4-(4-y-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8- (4-fluorophenyl)-7-mercapto-5,6,7,8-tetrahydropyrido[3,4-(1]pyrimidine-2,4-diamine. Example 17 6 N2-(4- (4-Chloro-1H-imidazol-1-yl,-3-methoxyphenyl)-N4-trimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidine-2,4-diamine

149653.doc •536- 201107311 2-O-7-V III-indolyl-7-phenyl-6,7-dihydro-57/-cyclopenta[d]D-biti-4-amine (121.2 mg , 0.461 mmol) and 4-(4-chloro-1β-imidazol-1-yl)-3-methoxyaniline (103 mg '0.461 mmol) in THF (1 mL) and acetic acid (1.000 mL) Heat at 80 ° C overnight. The reaction mixture was purified by reverse phase preparative HPLC to afford 7V2-(4-(4-chloro-1//--m. #·三氘Methyl_7_phenyl-6,7-dihydro-5//-cyclopenta[d]pyrimidine-2,4-diamine TFA salt (114.3 mg, 43%). LC-MS ❿ (M+H)+=450.0. 4 NMR (500 MHz, CDC13) δ ppm 8.86

(1H, s), 7.88 (1H, t, /=8.4 Hz), 7.22-7.31 (4H, m), 7.19 (1H, d, 7=8.9 Hz), 7.07 (3H, t, /=8.7 Hz) , 4.27 (1H, t, /=8.5 Hz), 3.73 (3H, s), 2.45-2.59 (1H, m), 2.38 (1H, d, /=7.6 Hz), 2.30 (1H, d, J=3.7 Hz), 1.95-2.06 (1H, m) 〇Examples 176A and 176B (S)-N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-f-oxyphenyl)_furnace_ Tris-methyl-7-n-yl-6,7-dichloro-5H-cycloindolo[d]bite-2,4-diamine• and (R)-~N2-(4-(4-chloro -1H-imidazol-1-yl)-3-methoxyphenyl)trioxin-7-benyl-6,7-dihydro-5 H-cyclopenta[d]pain η--2, 4-diamine

Purification of imidol-1-yl)-3-decyloxyphenyl)-#_trimethylphenyl-6,7-dihydro·149653.doc using palmitic supercritical fluid chromatography (SFC) -537- 201107311 5//-Cyclopenta[d]pyrimidine-2,4-diamine racemic mixture (133 mg, 0.206 mmol, from real! disease^7(5), giving 28.4 mg peak A ( Real score y 77(5^4) and 27.4 mg peak B (pass; //76jB). SFC **: Chiralpak〇J_ H(3〇x250 mm, 5 μΜ) '40% of C02 sterol (0· 1 〇 /. Diethylamine), 35 ° C, flow rate 70 mL / min, maintain Ιό min, 268 nm absorbance, injection 1 mL 22 mg / mL solution in methanol (multiple stack injection), peak A) = 5.0 min 'iR (peak B) = 11.2 min. The absolute stereochemistry of the individual enantiomers (7 7 M and 7 7 M) was not determined. LC-MS and 1H NMR analysis of the separated enantiomers Same as racemic (unloading 776). Example 177 2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino) 4-(methylamino) -8-phenyl-7,8-dihydroanthracene.

2-Gas-4-(decylamino)-8-phenyl-7,8-dihydroquinazoline-8-ol (25 mg) and 4-(4-chloro-1//-imidazole-1 A solution of 3-yl-3-methoxyaniline (29 mg) in dioxane (0.2 mL) and acetic acid (0.2 mL) was obtained. (The next heating was carried out for 4 hours. The THF was removed in vacuo and the residue was purified by EtOAc (EtOAc). += 475.26. iji NMR (TFA salt, 500 MHz, CD3OD) δ ppm 7.2-7.9 (m), 6.56 (1H, m), 6.18 (1H, m), 3.94 (3H, s), 3.20 (3H, s ), 3.10 (2H, m). Example 178 149653.doc -538 - 201107311 2_(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)_4_(decylamine) Base)-8-phenyl-5,6,7,8-tetrahydroanthracene

The title compound was prepared as a TFA salt in the same manner as described in Example 177. LC-MS (Μ+Η)+=477·28. NMR (TFA salt, 500 MHz, CD3OD) δ ppm 7.1-8.0 (m), 3.88 (3H, s), 3.18 (3H, s), 1.2-2.5 (6H, m) 0 Example 179 2-(4-( 4-Q-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-ol

4-(4-Chloro-1H-0m. sit-1-yl)-3-decyloxyaniline (37.1 mg, 0.166 mmol), 2-ox-4-(diamino)-7-benzene Base-6,7-dihydro-5H-cyclopenta[d] 0-denyl-7-ol (40 mg, 0.138 mmol), Pd2 (dba) 3 (5.06 mg, 5.52 μιηοΐ), xanphos (7.99 mg) A mixture of 0.014 mmol) and Cs2C〇3 (135 mg, 0.414 mmol) was heated overnight at 10 °C. By preparative HPLC (column: PHENOMENEX LUNA C18 3〇xl〇〇mm, solvent A = 10 mM ammonium acetate 95:5 H20/ACN solution, solvent B = 10 mM ammonium acetate 5:95 H20/ACN solution The crude product was purified to give the title compound (32 mg). LC-MS (Μ+Η)+=477·19. 4 NMR (TFA salt, 500 MHz, CD3OD) δ ppm 6.8-7.8 (m), 3.64 (3 Η, s), 3.30 (6 Η, s), 3.0- 3.2 (2H, m) and 2.4 (2H, m). Example 180 (6SJS)-2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dimethylamino)-7-phenyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-6-ol

The reaction was carried out in the same manner as described in Example 177 except that the purification methods were different. The crude product was purified by preparative TLC eluting with 50% EtOAc/hexanes LC-MS (M+H)+ = 477.13. Η NMR (500 MHz, CDC13) δ ppm 6.8-7.9 (m), 4.48 (1H, m), 4.07 (1H, m), 3.58 (1H, m), 3.50 (3H, s), 3.28 (6H, s), 3·12 (1H, m). Example 181 N-(4-(4-Ga-1H-imidazole-:yl)·, methoxyphenyl)_4_(3-nitroazetidin-1-yl)-7-phenyl_6 ,7_Dihydro-5Η_cyclopenta[d]pyrimidin-2-amine

IN 149653.doc -540· 201107311 The preparation A was reacted with the preparation α in the manner described in the example of the shell, and the preparation α was obtained to obtain Ν-(4·(4-chloro-1H_mi-l-based) )-3-Foxybenyl)-4-(3-pirohydrobutane-1-yl)_7_ cage^^_6,7_dioxin-5H-cyclopenta[d]octidine _2-amine. LC-MS (M+H)+=SD7 ο ιτ) 507.2. HNMR (500 MHz, gas 岣δ ppm 10.71 (d, J=i〇qa it ^ &gt; 19.84 Hz, 1 H) 8.50 (d, J=1.53 Hz, 1 H) 7.45 (4), J=8·85 , 3 Hz, 1 H) 7.24-7.40 (m, 5 H) 718_ (, 2 H) 5.12 (br. s.5 i H) 4.76-4.95 (m, 2 H) 4.71 (d 7=10·68 H&quot;1H) 4·35-4^ (^2H)3.BS(s53H)3,2(; /=14.65 Hz, 1 Η') λ m (αλ ' ^ · (dd, 7=19.99, 6.26 Hz , 1 H) 2.68- 2.85 (m, lH) 2.24-2.42 (m, lH). By arranging the eight-touch &amp; 曰斫 from the palm-shaped SFC layer to separate the individual enantiomers, the actual 181A and 181B. Example 182 N-(4-(4-Chloro-1H. aryl. sylylene) _3_methoxyphenyl)-4-(fluoroazetidin-1)yl-7-yl句-二气_5Η_cyclopenta(4) mouth n-amine

In a manner similar to that described in Example 8, the preparation of the oxime and the preparation were postaged to obtain Ν-(4·(4-气)Η·咪哇]•基)_3_methoxyphenyl) Gas nitrogen heterocyclic butyl group) - 7 - phenyl _6,7-dihydro-cyclopentanyl octazone. " Hall (_) += 491.2. 4 faces _MHz, gas pattern ♦ ppm 11.07 (b, s.51H) 8.30 (br. s&gt;, 1H) 7.45 (d, ^8&gt;55 149653.doc -541 - 201107311

Hz,2 Η) 7.38 (br. s·,3 Η) 7.33 (d, piece.88 Hz, 2 Η) 7,l3 7.31 (m,1 H) 5.50-5.61 (m,! h) 4.91 (br. s.,1 H) 4.7l (br s" 2 H) 4.43 (br. s·, 2 Η) 3·89 (br. s.,3 H) 3.14 (br. s.,ih) 3.03 (d, 7=18.92 Hz, 1 H) 2.75 (br. s., 1 H) 2.20-2.39 (my H). Examples 182A and 182B were obtained by separation of individual enantiomers by palm SFC chromatography. Example 183 N-(4-(4-Ga-1H-imidazole-1·yl)_3_methoxyphenyl)_4_(3-methoxy nitrogen % Heterocyclobutane-1-yl)-7-benzene Base dihydro-5H-cyclopenta[d]pyrimidine_2, amine OMe

In a manner similar to that described in J 8 in this way, the preparation of the oxime a and the preparation are reacted to pass to N-(4-(4-gas-iHUgy·decyloxyphenyl sulfoxy azetidine). -1_yl)_7_phenyl_6,7-dihydro_5H•cyclopentyrimidine-2-amine. LC_MS (M+H)+=5〇3 2.]h nmr (9) 〇, 蒇^ d) h ppm 7.73 (1 H, br. s.) 5 7.49 ^ Hj 7.30.7.35 (2

H&gt; m), 7.22 (4 H} t5 J=8.24 Hz), 7.04.7 07 (1 H, m), 7.00 (1 H' s), 6.90 (1 h, br. s.), 4.45-4.52 (2 H,m),4.33-4.39 (1 H, m), 4.16-4.23 (3 H, m), 3.57 (3 H, s), 2.98-3.07 (1 H, m), 2.85 2.96 (1 H , m), 2.55-2.67 (1 H, m, 7=13.28, 8.77, 8.77, 149653.doc •542- 201107311 4.58 Hz), 2.06-2.16 (1 H, m). Examples 183A and 183B were obtained by separating individual enantiomers by palm SFC chromatography. Example 184 N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_7-phenyl_4_(5&gt;8-oxo-2-azaspiro[3.4]xin- 2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine_

2-amine

2-(2-Ga-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)-5,8-monooxy-2-aziro[3.4]xin (Finish Gl) (23 mg, 0.067 mmol), 4 (4-chloro-1H-imidol-1-yl)_3_methoxyaniline (preparation a) (17.95 mg, 0.080 mmol), Dibenzylideneacetone) two (〇) (3 〇 6 mg, 3 34 μηιοί), (9,9-dimercapto-9H-dibenzopyran-4,5-diyl) bis(diphenyl Phosphine) (3.87 mg, 6.69 μηιοί) and sodium carbonate (14.18 mg, 0.134 mmol) in a mixture of dioxo (319 pL) / water (63, 7 μ! 加热) heated overnight at i ° ° C. Preparative HPLC (solvent A = 10% MeOH - 90% H20 - 0.1% TFA, solvent b = 90% MeOH - 10% H2O - 0.1% TFA, column: PHENOMENEX LUNA 3 〇 xl 〇〇 mm, S10, flow rate :40 ml/min '30%-l〇〇% B, 3 〇 minutes) to purify the crude product to give N_(4_(4-chloro-1H-imidazolyl)_3_methoxyphenyl)-7-phenyl _4_(5,8-Dioxy.2_azaspiro[3_4]oct-2-yl)_6,7-dihydro-5Η·cyclopenta[d]pyrimidin-2-amine TFA salt 149653.doc •543 - 201107311 (17 mg, 0.024 mmol, yield 35.5%). LC-MS (Μ+Η)+=531.1. NMR (500 ΜΗζ, -ί/) δ ppm 11.39 (s, 1 Η) 8.09 (s, 1 Η) 7.45 (d, 7=8.55 Hz, 1 Η) 7.35-7.42 (m,4 Η) 7.19-7.34 (m,1 Η) 7.15 (s,2 Η) 4.73 (br. s.5 2 H) 4.51 (br. s., 2 H) 4.42 (dd, /=8.70, 4.12 Hz, 1 H) 4.09 (d, /=3.66 Hz, 4 H) 3.87 (s, 3 H) 3.12 (dd, 7=14.34, 7.02 Hz, 1 H) 2.90-3.05 (m, 1 H) 2.67-2.81 (m, 1 H) 2.29 (ddd, /=9.16, 4.43, 4.12 Hz, 1 H) 〇 Example 185 1-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylamino)_7•phenyl-6, 7_Dihydro-5H-cyclopenta[d] η 密-4-yl)azetidin-3-one

Ν-(4-(4-Chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(5,8-dioxo-2-aziro[3· 4] Oct-2-yl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidin-2-amine (Example 184) (12 mg, 0,023 mmol) in acetone (161 μί) / water (32.3 The mixture in μί)/70% HC104 (32.3 gL) was heated overnight at 50 °C. The crude product was purified by preparative HPLC to give (2-(4-(4-chloro-1 Η-imidazol-1-yl)-3-methoxyphenylamino) -7 phenyl _ _ _ Dihydro-5Η-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one (2.5 mg, 4.62 μιηοΐ, yield 20.5%). LC-MS (Μ+Η)+=487.2. 'H NMR (500 ΜΗζ, chloroform δ ppm 7.57 (s, 1 Η) 7.42 (t, J=7.63 Ηζ, 3 Η) 7.26- 149653.doc -544- 201107311 7.38 (m,3 Η) 7·12-7 ·26 (m,2 H) 7 〇〇7 i2 (m,ih) 5 23 (br. s., 4 H) 4.43 (b, s., 1 H) 3.68-3.79 (m, 3 H) 3.10- 3.27 (m, 1 H) 2.93-3.08 (m, 1 H) 2.71-2.84 (m, 1 H) 2.37 (br. s., 1 H). Example 186 1 (2-(4-(4-gas-) 1H-Mimi. Sodium-1-ylmethoxyphenylamino)_7_(4_Phenyl)-6,7-dihydro-5H-cyclopenta[Bisting·4-yl)_3_Methyl Gas heterocyclic φ 曱 曱 nitrite

CI was prepared in a manner similar to that described in Example 184 by combining the preparation core with the preparation A' to give 1-(2-(4-(4-chloro)H-isoxazole small) fluorenyloxyphenylamino) -7-(4-Fluorophenyl)-6,7-dihydro-5Η·cyclopenta[d] ♦ pyridine-4-yl)-3-methylazetidin-3-indenecarbonitrile. LC-MS (M+H)+ = 530.1. 4 NMR (500 MHz, chloroform δ ppm u 5 〇 (br s , 1 H) 8 18 s, 1 H) 7.46 (d, / = 7.63 Hz, 1 h 7.12-7.31 (m,3 H) 7.06 (br. s·,3 H) 4.99 (br. s., 1 H) 4.72 (br. s., 1 H) 4.43 (br. s.5 2 H) 4.28 (br. s., 1 H) 3.88 (s, 3 H) 3.11 (br. s., 1 H) 3.00 (br. s., 1 H) 2.76 (br. s·,1 H) 2.28 (d , */= 5.49 Hz, i H) 187 (s, 3 H). Example 1H7 N-(4-(4-Chloro-1H-imidazo-indolyl)_3_f-oxyphenyl)_4 (3-ethoxy nitrogen 149653.doc •545 · 201107311 杂王衣丁烧基)- 7-(4-M, its paper base)-6&gt;7-dihydro-5H-cyclopenta[d]pyrimidine·I

OEt

The preparation Had and the preparation VIII were combined in a manner similar to that described in Example 184 to give hydrazine-(4.(4' singular (tetra)+ s-methoxyphenyl ethoxy azetidinyl) )_7_(4^phenyl)_6,7_: hydrogen·cyclodecano(4)pyrimidin-2-amine. LC_MS (M+H)+=535 1. lH nmr (5〇〇MHz, gas-like δ δ ppm 11.77 (br_ s., ! Η) 7·74 (d, J=4 58 Hz, 1 H) 7.52 (br. s., 1 H) 7.34-7.41 (m, i H) 7.12-7.30 (m, 2 H ) 7.06-7.12 (m,1 H) 7.03 (br. s.,2 H) 4.77 (br. s., 1 H) 4.51 (br. s., 2 H) 4.49 (d, 7=5.49 Hz, 1 H) 4.36 (br. s., 1 H) 4.24 (br. s., 1 H) 3.85 (d, /=4.88 Hz, 3 H) 3.55 (dd, J=e 71 5.49 Hz, 2 H) 3.12 ( Br. s.5 1 H) 2.99 (br. s., l H) 2.68 (br s., 1 H) 2.23 (br. s.,1 H) 1.21-1.37 (m,3 H). Palm chromatography on SFC to separate individual enantiomers gave Examples 187A and 187B. Example 188 Ν·(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)· 7phenyl-4-oxo-2-aziro[3.4]oct-2-yl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidinamine 149653.doc • 546· 201107311

N-(4-(4-Ga-1H-m.. Sodium-4-(5-oxo-2-azaspiro[3.4]oct-2-) was obtained in a similar manner to the one described in Example 184. Formula, the preparation of Gm and the preparation of 1-yl)-3-methoxyphenyl)-7-benzidine-2-amine. LC-MS (M+H)+= 529. 7-Dihydro-5H-cyclopenta[d]pyrimidine H NMR (500 MHz, gas δ δ ppm 10.85 (br. s., s·, 4 H) 7.20-7.39 (m, 4 H) 4 56 H) 8.36 (br. s.,1 Η) 7.49 (br. (br. s.,3 Η) 3.92-4.10 (m, 3 h) H) 3.00 (d, J=12.51 Hz, 1 h) «7=6.87 Hz,3 H) 2.06 (d, "7=6.41 Example 18 9 (d, ./=9.16 Hz, 1 H) 4.41 3·87 (S} 3 H) 3.11 (br. s., 12.73 (br. s.,1 H) 2.26 (t, Hz, 2 H). Methoxy-based amino)-7-(4-fluoro-4-yl)-3-methylazetidine_

1-(2-(4-(4-Chloro-1H-imidazo-yl)-^phenyl)-6J-dihydro-5H-cyclopenta[d] mouth 3-0

The preparation Hae and the preparation A were combined in a manner similar to that described in Example 184 to give 1-(2-(4-(4-chloro-1), oxime-1-yl)-3_曱. Oxyphenylamine storm)-7-(4-fluoro-based)-6,7-monohydro-5h_瑷々,, r &amp;open [d]pyrimidin-4-yl)_3_mercapto 149653 .doc -547- 201107311 Azetidin-3-ol. LC-MS (M+H)+=521.1. 4 NMR (400 MHz, MeOD) δ ppm 7.93 (d, J = 1.51 Hz, 1 Η) 7.65 (d, J = 2.26 Hz, 1 H) 7.26-7.44 ( m,4 H) 7.01-7.26 (m,4 H) 4.48-4.68 (m, 2 H) 4.44 (dd, J=9.03, 6.78 Hz, 1 H) 4.18-4.38 (m, 2 H) 3.90 (s, 3 H) 3.15 (dd, J=5.27, 3.76 Hz, 1 H) 2.96-3.06 (m, 1 H) 2.62-2.82 (m, 1 H) 2.12 (dddd, J=13.18, 8.85, 6.46, 6.15 Hz, 1 H) 1.55-1.66 (m, 3 H). Examples 189A and 189B were obtained by separating individual enantiomers by palm SFC chromatography. Example 190 N-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)_4_(3_fluoro_3_methylazetidin-1-yl)- 7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d] 喊口定-2-amine

1-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-(4-fluorophenyl)-6,7-dihydro-5H- A solution of cyclopenta[d] guan-4-yl)-3-mercaptocyclobutan-3-ol (35 mg, 0.067 mmol) in CH2C12 (volume: 274 μΐ) was cooled to -78 °C . To this mixture was added dropwise [bis(2-methoxyethyl)amino]sulfur trifluoride (13-62 μM, 0.074 mmol), and the solution was stirred at -78 ° C for 30 minutes' and then warmed to 〇°c and stir for another hour. With saturation 149653.doc •548- 201107311

The NaHC〇3 solution and brine were quenched. The aqueous layer was extracted with cHAh. The organic layer was dried over Na 2 SO 4 and concentrated. The crude product was purified by preparative HPLC to give Ν-(4-(4·chloro-1H-imidazol-1-yl)-3 methoxyphenyl)_4_(3_fluoro-3-methylazetidine Alkano-indole-yl)_7_(4-fluorophenyl)_6,7-dihydro·5Η_cyclopenta[d]. dense. D-2-amine TFA salt (4. 〇 mg, 5 65 μηι〇ι). Lc_ms (M+H) = 523.1. NMR (5 〇〇 MHz, gas _d) δ 1138 (br. s.,1 Η) 8.14 (s,1 η) 7.43-7.54 (m,1 Η) 7.30-7.38 (m,

1 H) 7.20-7.26 (m, 3 H) 7.16 (s, 1 H) 7.06 (t, J=7.78 Hz, 2 H) 4.78 (br. s.3 l H) 4.54 (br. s., 2 H ) 4.42 (br. s., 2 H) 3.88 (s, 3 H) 3.12 (d, J-7.93 hZ) 1 H) 3.00 (br. s., 1 H) 2.75 (br. s., 1 H) 2.21-2.34 (m,! H) 178_182 (br s,3 H). Example 191 N (4 (4 chloro-in-imilyl)·3_decyloxyphenyl fluorophenyl)_ (methoxy 3 3 azoazetidine small) hydrazine dichloride &amp; and

[d]pyrimidine-2-amine

Similar to the F substance A in Example 184, the N♦(4) formula was prepared and the preparation was prepared - cyclopentyl: di = heterocycle

private. LC_MS (M+H)+ = 535.1. NMR 149653.doc -549- 201107311 (500 MHz, chloroform-J) δ ppm 11.75 (d, /=4.27 Hz, 1 Η) 7.83 (d, "7=1.22 Hz, 1 H) 7.47 (d, /=1.83 Hz,1 H) 7.44 (d, 7=8.55 Hz, 1 H) 7.15-7.33 (m, 4 H) 7.03 (t, 7=7.63 Hz, 2 H) 4.53 (d, "7=8.85 Hz, 1 H ) 4.24-4.43 (m,3 H) 4·06·419 (m,i H) 3.86 (s, 3 H) 3.34 (s, 3 H) 3.13 (ddd, /=12.67, 6.56, 6.41

Hz, 1 H) 3.01 (ddd, *7=15.95, 4.81, 4.58 Hz, 1 H) 2.70 (td «7=9.46, 3.66 Hz, 1 H) 2.24 (tt, "7=8.96, 4.31 Hz, 1 H ) 1.63 (s, 3 H). Examples of ® 191A and 191B were obtained by separating individual enantiomers by palm SFC chromatography. Example 192 7-(4-Fluorophenyl)-4-(3-methoxy-3-methylazetidin-y-yttrium-yl)-N (3-methoxy-4-(3-methyl) -1H-1,2,4-triazole·:t-yl)phenyl)_6&gt;7-dichloro 5H-cyclopenta[d]pyrimidine-2-amine

The preparation Haf and the product D were combined in a manner similar to the stream + _ &amp; in Example 184 to give 7-(4-fluorophenylindole (3~methoxy-3-methylazacyclo). Butane·yl)·Ν-(3-methoxy-4-(3-methylthiazol-1丞-1,2,4-triazol-1-yl)phenyl)-6, dihydro-5Η- Cyclopenta[d]pyrimidine_2 month female. LC-MS (Μ+Η)+=516·1.1 NMR (500 ΜΗζ, gas imitation-heart again} 0 PPm 11.77 (d, J=3.97 Hz, 1 ] 149653.doc - 550. 201107311 8.88 (s, 1 Η) 7.69 (d, J=8.55 Hz, 1 H) 7.52 (dd, J=8.85, 2.14 Hz, 1 H) 7.47 (s, 1 H) 7.23 ( t, J=5.49 Hz, 2 H) 7.03 (t, /=8.39 Hz, 2 H) 4.45-4.58 (m, 1 H) 4.35 (d, /=4.58 Hz, 2 H) 4.27 (d, J=7.63 Hz, 1 H) 4.10 (d, J=l〇.〇7 Hz, 1 H) 3.85-4.04 (m, 3 H) 3.33 (s, 3 H) 3.05-3.20 (m, 1 H) 2.92-3.05 ( m,1 H) 2.63-2.79 (m,1 H) 2.45-2.59 (m, 3 H) 2.23 (td, «7=8.39, 4.27 Hz, 1 H) 1.57-1.72 (m,3 H). Separation of the individual enantiomers by palm SFC chromatography gave Examples 192A and 192B. Example 193 7-(2,4-Difluorophenyl)-N2-(3-methoxy-4-(3- Mercapto-1H-1,2,4-tris-7-yl)phenyl)-N4-mercapto-6,7-dihydro -5H-cycloindolo[d]pyrimidine-2,4-diamine

2-Gas-7-(2,4-difluorophenyl)-indolyl-6,7-dihydro-5indole cyclopentane is called biting-4-amine (153 mg, 0.517 mmol), 3 -decyloxy-4-(3-indolyl-1H-1,2,4-tris(yt-1-yl)aniline (211 mg, 1.035 mmol) and H2S〇4 (44.1 μΐ, 0.828 mmol) in N The mixture in -methyl-2-pyrrolidone (volume: 2070 μΐ) was heated overnight at 100 °C. Saturated NaHC03 was added slowly and extracted with EtOAc (3 times). The combined organic layers were dried with Na2SO4 and concentrated. By preparative HPLC (solvent A=10% MeOH-90% H20-〇.l% 149653.doc •551 · 201107311 TFA, solvent B=90% MeOH-10% H20-〇.l% TFA, column: PHENOMENEX LUNA 30x100 mm, S10, flow rate: 4〇ml/min '30%-100°/〇B '15 minutes) to purify the crude product to give 7_(2,4-difluorophenyl)-N2-(3 -曱oxy-4-(3-methyl-1H-1,2,4-tris-i-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d 〇 α 定 -2,4-diamine TFA salt (287 mg '0.447 mmol, yield 86%). LC-MS (M+H)+ = 464.1. NMR (500 MHz, | 谬-d) δ ppm 11.54 (1 H, s), 9.22 (1 H, s)} 7.75 (1 H, d, J=8.85 Hz), 7.65 (1 H, s), 7.49 (1 H, d, J=8.85 Hz), 7.13-7.21 (1 H, m), 6.79-6.91 (2 H, m), 6.11 (1 H, d, 7=4.27 Hz), 4.56-4.63 (1 H, m), 3.97 (3 H, s), 3.23 (3 H, d, 7=4.27 Hz), 2.84-2.93 (1 H, m), 2.71-2.81 (2 H, m), 2.62 (3 H , s), 2.19-2.28 (1 H, m).

Examples 193A and 193B (S)-7-(2,4-difluorophenyl)-N2-(3-methoxymi,2,4-triazol-1-yl)phenyl)-N4-methyl -6,7-dioxin_5H-cyclopenta[d]pyrimidine-2,4-diamine oxime (R)-7-(2,4-difluorophenyl)-indole 2-(3-decyloxy 4-(3-methyl-lH-l,2,4-triazole-l-yl)phenyl μN4-methyl-6,7-dihydro·5H-cyclopenta[d]pyrimidine-2, 4-diamine

149653.doc 201107311

Purification of 7-f2〆-二广哀基-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-) by palmar supercritical fluid chromatography (SFC) Triwax-l-yl)phenyl)-N4-methyl-6J-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine in addition to the m compound (grass 793), Peak A (f 7PM) and peak B (not M35). SFC

Method: Chiralpak OJ-H (3〇xl50 mm), 30% sterol (0.1% diethylamine) in C02, 100 bar, flow rate 50 mL/min, maintained for 12 minutes, 268 nm absorbance, injection 2.0 mL 10 mg /mL solution in methanol, (peak Α) = 4·7 minutes 'iR (peak B) = 9.6 minutes. The absolute stereochemistry of the individual enantiomers (real/P3乂 and 7935) was not determined. 193A: LC-MS (M+H)+= 446.2 ° LC Rt 13.03 min (Waters Sunfire 4.6x150 mm, 10% to 100% B in 15 minutes A, 1.5 mL/min (A is 90:10:0.1) Water: MeOH: TFA; B is 90:10:0.1 MeOH: water: TFA)). NMR (500 MHz, M^rd) 6 ppm 8.46 (1 H, s), 8.04 (1 H, s), 7.51 (1 H,d, "7=8_55 Hz), 7.04-7.13 (2 H,m) , 6.78-6.87 (3 H,m), 4.42-4.50 (1 H, m), 3.68 (3 H, s), 3.13 (3 H, s), 2.62-2.79 (3 H,m), 2.49 (3 H, s), 1.96-2.08 (1 H, m) 〇 Example 194 6-(2,2-Difluoroethyl)- then-ethyl---(3-fluoro-4-(5-methyl) 1 -1,2,4-tris-yl-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydrogen 唆[4,

149653.doc -553 - 201107311 The preparation AEo was reacted with difluoro-2-indole, potassium pentoxide and bismuth steel in dmf at 80 ° C to obtain 6-(2,2-difluoroethane). -N4-ethyl-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-8-phenyl-5,6 7,8-tetrahydro D was bitten and [4,3-d] was sprayed with-2,4-diamine (Example 194). LC-MS (M+H)+ = 509.4 实例 The individual enantiomers were separated by chromatography on the palm of SFC to give examples 194A and 194B. Example 195 (^ &gt; · monoethyl)-N 4-ethyl-N2-(3- gas- 4-(3-methyl-1H-1,2,4-tris-s--1-yl)benzene -8-phenyl-5,6,7,8-tetrahydroindole and [4,3-d] mouth bite - 2,4-diamine

The preparation AEm was reacted with difluoro-2-iodoethane, potassium carbonate and sodium sulphate in DMF at 80 ° C to give 6-(2,2-difluoroethyl)-N4-ethyl-N 2 -(3-Fluoro-4-(3-indenyl-1H-1,2,4-triazol-1-yl)phenyl)·8-phenyl-5,6,7,8·tetrahydropyridine [4,3-d]pyrimidine-2,4-diamine (Example 195). LC-MS (Μ+Η)+= 509.2. Examples 195 and 195 are obtained by separating individual enantiomers by palm SFC chromatography. Example 196 149653.doc -554- 201107311 N4-ethyl 42-(3-methoxy-4-(4-gas·1H_13, imidazoheptyl)phenyl)_ 8-phenyl-6-(2,2 ,2-trifluoroethyl)-5,6,7,8-tetrahydro^ and ^本_ bite-2,4-diamine

In a manner similar to the cracking material ΑΕρ and the reward 146, the method of 10,000 is used to convert the preparation AEk

Formation into N4-ethyl-N2-(3-methoxy-4_(4-nitro-13-isoxazolyl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl) -5,6,7,8-four ft πμμ &amp; , 0 four 虱. Bis-[4,3_d]pyrimidine-2,4-diamine (Example 196). LC-MS (M+H)+ = 558 2 </RTI> </ RTI> </ RTI> </ RTI> The individual enantiomers 196A and 196B were separated by chromatography on a palm of SFC. Example 19 7 N4-Ethyl-N2-(3-methoxy-4-(4-Ga-1H-13-imidazolyl-4-yl)phenyl) 8-phenyl-6-(2,2-difluoroethyl) -5,6,7,8-tetrahydropyrido[43d]pyrimidine 2,4-diamine

The preparation AEk was reacted with difluoro-2-anthracene, potassium carbonate and sodium iodide in DMF at 80 C to give N4-ethyl-N2-(3-methoxy_4_(4-chloro- 1H-149653.doc • 555 - 201107311 13-Imidazol-1-yl) stupyl)-8-phenyl-6-(2,2-difluoroethyl)-5,6,7,8-tetrapyridine And [4,3-d]pyrimidine-2,4-diamine (Example 197). LC-MS (M+H), 540.2 °. The individual enantiomers were separated by chromatography on the palm of SFC to give Examples 197A and 197B. Example 198 8-(4-Fluorophenyl)-N2-(3-methoxy-4-(3-methyltrisyl)phenyl)-N4,6-dimethyl-5,6,7, 8-tetrahydropurine bite [4,3-d]pyrimidin-2 4 diamine

F Reacts Preparation D with Preparation AHa in a manner similar to that described in Example 8 to give 8-(4-fluorophenyl)-N2-(3-decyloxy_4_(3·indenyl)H_ 1,2,4-triazole-i-yl)phenyl)_Ν4,6·dimercapto-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4- Diamine. LC-MS (M+H)+ = 475.2. The racemic mixture was separated by palm chromatography to give enantiomers 198A and 198B. Example 199 8-(4-Fluorophenyl)-N2-(3-methoxy-4-(5-methyl-1H-12,4_tris.-s-yl)phenyl>-, then, 6- Dimethyl-5,6,7,8-tetrahydropyrido[4,3_幻0密.定_24 Diamine 149653.doc • 556- 201107311

The preparation DD was reacted with the preparation AHa in a manner similar to that described in Example 8 to give 8-(4-fluorophenyl)-N2-(3-methoxy-4-(5-fluorenyl-n) 1,2,4-Tris-7-yl)phenyl)_N4,6--indolyl-5,6,7,8-tetrahydroindole ratio. Ding and [4,3-d] mouth bite-2,4-diamine. LC-MS (M+H) = 475.2. Enantiomeric examples 199 and 1996 were obtained by separation of the racemic mixture by palm chromatography.

Example 2QQ (±)-2-(4-(4-Chloro-1H-imidazol-1-yl)-nemethoxyphenylamino)-4-(methylamino)-7-phenyl-6, 7-dihydro-5H-cyclopenta[d]pyrimidin-5-one

2-Gas-4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]a aceton-5-one (Preparation AN) (7 mg) and 4-(4_Gas-1//-Imidazol-1-yl)-3-decyloxyaniline (Preparation A) (7 mg) in THF (0-2 mL) and sulfuric acid (4 mg) Heat at °C for 12 hours. The THF was removed in vacuo and the residue was crystallised eluted eluted elute LC-MS (M+H)+=461.12. 4 NMR (500 MHz, CD3OD) δ ppm 7.80 (m), 7.1-7.4 (m), 4.50 (1H, m), 149653.doc - 557 - 201107311 3.25 ( 1H, m), 2.56 (1H, m), 3.50 (3H, s) and 3.19 (3H, s). Enantiomeric examples 200A and 200B were obtained by separating the racemic mixture by palm chromatography. Example 201 (E)-2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7 -dihydro-5H-cyclopenta[d]pyrimidin-5-one oxime-methyl

0.15 Torr of Example 200 iPrOH solution was heated with 4 equivalents of decylamine hydrochloride at 85 °C for 3 hours. Reverse phase HPLC was carried out to give the desired material as a TFA salt. LC-MS (M+H)+ = 490.2. The mixture was isolated by chromatography to afford enantiomers 201A and 201B. Example 202 2-(4-(4-Gas-1H-imidazol-1-ylmethoxyphenylamino)_4·(methylamine basic group - 6,7-di-molyte-5H-cycloindolo[d] σ 唆-5 - alcohol OMe, NH nu

Ci-^vn NaBH4 was added to a solution of Example 201 in methanol at room temperature, and the mixture was stirred at room temperature for 1 hour. Treatment of the reactants with EtOAc/H20 gave the desired product as a white solid. LC-MS (M+H)+= 149653.doc -558-201107311 463.1. Example 203 N2-(4-(4-Chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4.methyl-8_phenyl-5,6,7,8-tetrahydroquin Oxazoline-2,4-diamine

CI-^N

</ RTI> <RTIgt; ), 7.24- 7.32 (4 H,m), 7.16-7.23 (1 H, m), 7.08-7.14 (2 H,m), 7.00 (2 H,s), 6.70 (1 H,dd,J=8.3 , 2.0 Hz), 4.71 (1 H,d, J=3.〇

Hz), 4.03 (1 H, t, J=5.6 Hz), 3.41 (3 H, s), 3.12 (3 H, d5 J=4.8 Hz), 2.30-2.48 (2 H,m), 2.09-2, 22 (1H,m, J=13.05 9.7, 6.2, 3_3, 3.1 Hz), 1.74-1.96 (3 H, m) 分离 Separation of the racemic mixture by palm chromatography to give an enantiomer 203 six and 2036. Example 2Q4 1-(2-Methoxy-4-(4-(decylamino)-7-phenyl-6J-dihydro-5H_cyclopenta[d]pyrimidin-2-ylamino)phenyl )-1Η-imidazole-4-carbonitrile

To 2-chloro-1^-methyl-7-phenyl-6,7-dihydro-511-cyclopenta[(^]. 密(1定-4-amine 149653.doc •559- 201107311 (preparation Add 丨_(4.Amino-2-yloxyphenyl)_ih-methanol to a solution of di- smolder (ratio: 1, volume · 1013 μM) in a solution of gamma (150 mg, 0.578 mmol). 4-carbonitrile (preparation aa) (i24 mg '0.578 mmol) and AcOH (ratio: 1.000 'volume: 1013 μl). The resulting mixture was brought to 100 ° C in a sealed vial and taxed overnight. The mixture was extracted with EtOAc (3×1 mL).EtOAc. Purification with acetonitrile/h2 oxime/ammonium acetate to give 1-(2. methoxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5 fluorene-cyclopenta[d] Pyrimidin-2-ylamino)pyridyl)_1Η_imidazole_4_phthalonitrile (57 mg '0.130 mmol' yield 22.56%). LC-MS (Μ+Η)+= 438.2.*Η NMR (500 MHz ,MeOD) δ ppm 8·02_8 〇8 (2 Η, m), 7.90-7.94 (1 Η, m), 7.31 (2 Η, t, /=7.63 Hz), 7.16-7.24 (4 Η,m) 6.99 (1 Η, dd, *7=8.55, 2.14 Ηζ), 4·18 (1 η, t, 7=8.09 Hz), 3.56 (3 Η, s), 3.07 (3 Η, s), 2.76-2.84 (1 Η, m), 2.59-2.74 (2 H, m), 1.98-2.05 (1 H, m). Separation of the racemic mixture by palm chromatography affords the enantiomer example 204A and 204B. Example 205 N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl·4_(14_dioxo-7-azaspiro[4·4 ]壬-7-yl)-6,7-dihydro-5 η-cyclopenta[d]pyrimidin-2-amine 149653.doc • 560· 201107311 A, which gives N-(4-(4-chloro) _Imidazolyl-4-(1,4-oxo-7-azaspiro[4 4] fluorene-[d] ° 密定定-2-amine. LC-MS (M+H)+=

The preparation was carried out in a manner similar to that described in Example 184, and the preparation of the compound &lt;RTI ID=0.0&gt;&gt; Pentagon = 545.1. 4 NMR (500 MHz,

MeOD) δ ppm 7.89 (1 H, s), 7.62 (0.5 H, br. s.), 7.53 (0.5 H, br. s.), 7.37-7.45 (4 H, m), 7.32-7.36 (1 H , m), 7.30 (2 H, d, 7 = 7.63 Hz), 7.23 (0.5 H, d, J = 7.63 Hz), 7.14 (0.5 H, d, 7 = 7.32 Hz), 4.40-4.47 (1 H, m), 4.25 (1 H, br. s.), 3.96-4.14 (6 H, m), 3.88 (4 H, br. s.), 3.34-3.46 (1 H, m), 3.28 (1 H, Br. s.), 2.69-2.79 (1 H, m), 2.24-2.32 (1 H, m), 2.09-2.23 (2 H, m). Example 206 1-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclo Pentative [d]pyrimidine _4_yl)pyrrolidin-3-one

N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4- 146653.doc •561 - 201107311 (I,4-dioxo -7-azaspiro[4.4]dec-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 205) (37 mg, 0.068 mmol) and HCl (272 A mixture of μί, 0.272 mmol) in THF (339 pL) was heated at 60 ° C overnight. Concentrate to remove THF and add acetone (339 μιη) and HCl (272 pL, 0.272 mmol) to the mixture. The mixture was heated at 60 ° C for 6 hours. By preparative HPLC (solvent A = 10% MeOH - 90% H2O - 0.1% TFA, solvent B = 90% MeOH - 10% H2O - 0.1% TFA, column: PHENOMENEX LUNA 30 x 100 mm, S10, flow rate: 4 Torr) The crude product was purified by ml/min, 350/〇-100% B, 40 min), followed by preparative HPLC (column: PHENOMENEX LUNA C18 30x100 mm, solvent A = 10 mM acetic acid 95:5 H2O/ACN Solution, solvent B = 10 mM acetic acid 5:95 H20/ACN solution, flow rate: 4〇mi/min, 30°/.-100% B, 35 minutes) Purification to give 1-(2-(4- (4-gas _ 1Η-σ米D sitting-1-yl)-3 -nonyloxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 4-base). Biloxidin-3-one (2.0 mg, 3.59 μιηοΐ, yield 5.290/〇). LC-MS (Μ+Η)+=501·3. Example 207 4-(8-(4-Fluorophenyl)-4·(methylamino)-6-(methylsulfonyl)_56J&gt;8_tetraqi, ° pyridine[4,3-d]pyrimidine -2-ylamino)benzophenone

149653.doc • 562·201107311 The title compound was obtained by the general procedure described for the preparations AGj, AGk and AGp using 4-aminobenzonitrile and the preparation AGa. 1^- MS (M+H)+=453.2. NMR (400 MHz, DMSO-i/) δ ppm 9.25 (s, 1H) 7.85 (d, 7 = 8.80 Hz, 2H) 7.55 (d, J = 8.80 Hz, 2H) 7.25-7.29 (m, 2H) 7.10- 7.17 (m, 3H) 4.05-4.24 (m, 3H) 3.53-3.63 (m, 2H) 2.95 (d, *7 = 4.4 Hz, 3H) 2.95 (s, 3H). Example 208

N2-(4-(4-(Difluoromethyl)-1Η-mito-1-yl)-3-methoxyphenyl)_7_(4-fluoro-based)-indole 4-methyl-6,7 - one gas -5H-cyclopenta[d] v dense bite-2,4-diamine

The preparation EE was reacted with the preparation Hh in a manner similar to that described in Example 8 to give N2_(4_(4-(:fluorophenyl) methoxymethoxyphenyl)-7-(4-fluorobenzene -N4-methyl_6,7-dihydro-5H•cyclopenta(4)pyrimidine _ 2,4-amine. LC-MS (M+H)+=48l.l. NMR (500 MHz,

MeOD) δ ppm 8.19 (s 1 Η, 7" i ti) 7.75 (br. s., 1 H) 7.71 (s, 1 H) 7.45 (dd, /=8.55, 3.05 H7 i tt,,,

Hz,1 H) 7.31 (ddd, J=8.47, 5.26, 2.75 Hz, 2 H) 7.19-7 26 i lt,... •zo Cm, 1 H) 7.15 (td, J=8.77, 2.90 Hz, 2 H) 6.83 (t, «7=55 Hz 1ΙΉ 4 &lt; i /"·· 》 , 4.51 (d, J=2.75 Hz, 1 H) 3.91 (d, «7=3.05 Hz, 3 H) 3.18 id nc TT , } lQ) ^3.05 Hz, 3 H) 2.92 (d, J=9.16 Hz, 1 H) 2.76-2.85 (m 2 ΡΠ , ιλ 〇),, z 2.10-2.20 (m,1 H). 149653.doc - 563 - 201107311 Example 209 N2_(3-methoxy-4-(丨田* 1τ methyl-1Η-pyrazol-4-yl)phenyl)-m-methyl-7- its ^^ _ soil-, -dioxa-5H-cyclopenta[d]pyrimidine-2,4-diamine

The preparation A was reacted with the preparation Ga in a manner similar to that described in Example 8 Φ, _p T to give Ν2-Π-甲备# (methoxy-4-(1-methyl·1Η_° ratio) Zin-4-yl)phenyl)_

Ν4-Methyl-7-phenyl _6 7 _ &amp; CTT soil ~ plant-H-5H-cyclopenta[d]pyrimidine-2,4-diamine. LC MS (M+H) =425.4 〇&gt;H NMR (400 MHz, M^-d) δ ppm 7-84 (1Hs d^=2·01 Hz), 7.81 〇Hj s), 7.74(1H,s ) 5 7.32 (3 H, dd, 7-13.55, 7.78 Hz), 7.19-7.26 (3 H, m), 7.07 (1 H, s)' 6.78 (1 H, dd, /= 8.28, 2.01 Hz), 4.60 (1 H,q,7=4.52

Hz), 4.16-4.23 (1 H, m), 3.91 (3 H, s), 3.64 (3 H, s), 3.11 (3 H,d,J-5.02 Hz), 2.58-2.76 (3 H,m ), 2.00-2.11 (1 H, m). Example 210 149653.doc N-(2-(4-(4-Chloro-1H-imidazolidinyl)-1-yloxyphenylamino)-7-phenyl-6,7-dihydro-5H_ Cyclopenta[d]pyrimidine_4_kib N methylmethanesulfonamide

Preparative G was reacted at 0.9 °C with 0.9 equivalents of [VIeS〇2NHMe, 〇" equivalent pd (〇Ac) 2, • 564 · 201107311 0.15 equivalents of xanphos and Cs2C〇3. Subsequent addition of σ Preparation A gave the title compound. LC-MS (Μ+Η)+=525.4. '

7 ^ NMR (400 MHz, DMSO-ύ?) 6 ppm 9.79 (s, 1 Η) 7.75-7 ι-η , • ''(m.,2 Η) 7.45 (s,1 Η) 7.32-7.35 (m , 2 Η) 7.23-7.27 , ττ vu,4 JJ) 7.16-7.18 (m, 1H) 4.35 (t, 7=8.80 Hz, 1 H) 3.40 . „ j H) 3.31 (s, 3 H) 2.94-3.06 (m, 2 H) 2.57-2.61 (m, 1 H) 2 5i (s 3 H) 2.04-2.08 (m, 1H). 'Example 211 N-(2-(4-(4-气-1H-咪)嗤-1-yl)-3-methoxyphenylamino)_7 phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methanesulfonamide

The title compound was prepared as in Example 21, substituting ΜβΟ, ΝΗ2. 1^-]\48_+11)+=511.0.11^峨(400]^2,〇]\^0-Α δ ppm 9.51 (S,1 H) 7.73-7.76 (m,2 H) 7 4l ( s, [h) 7.16-7.31 (m, 8 H) 4.21 (ts 7=8.4〇Hz5 1 H) 3.54 (s, 3 H) 3.41 (s,3 H) 2_88_2.93 (m,2 H) 2 69 2 73 (m, ih)' i 9i_ 1.97 (m, 1H). Example 212 Κ2-(4-(4-chloromethoxyphenylamino)phenyl-6,7-dihydro-5H-cyclo Pentacene [d] yin, 4 _) 1 methyl ethanoamine 149653.doc - 565 - 201107311

The intermediate Ga is reacted with p-nonylphenylphenylamine in the manner of the preparation Gd. Coupling with preparation a under the conditions of Example 184 followed by treatment with TFA gave the C4NH2 compound. The named compound was obtained by reacting with AcCl at ambient temperature for 4 hours in di-hexane and dipEa. Lc ms (M+H)+=489.2. NMR (400 MHz, DMSO-equal δ ppm 9 89 (s, 1H), 7.92 (s, 1 Η), 7.75 (s, 1 Η), 7.44 (s, 1 H), 7 36-7 12 ( m, 7H), 4.38 (t, / -8.6 Hz, 1 H), 3.51 (s, 3 H), 3.33 (s 3H) 2.81 (t, /=7.4 Hz, 2 H), 2.59-2.55 (m, 1H), 2.17 (s, 3 H) 2.03 (dd, J = 8.8, 12.4 Hz, 1H). Example 213 Ν-(2·(4-(4-Ga-1H-imidazol-1-yl)-3- Methoxyphenylamino)-7-phenyldihydro 4H-cyclopenta[d]bitate-4-yl)-N-acetamide

To the solution of the intermediate Ga was added 15 equivalents of AcCi and 2 equivalents of dipea and refluxed for 3 days. The resulting product was coupled to the preparation a by the method of Example 184 to give the title compound. LC-MS (M+H)+=475.2. 4 NMR (400 MHz, DMSO-i/) δ ppm 7.86 (s, 1 H) 7.54 (s., 1 H) 7.35 149653.doc •566· 201107311 (d ,·/-8.40 1 Η) 7.23-7.30 (m,2 Η) 7.04-7.21 (m,6 Η) 6 73 6.76 (m,1H) 4.26 (t, "7=8.00 Hz, 1 Η) 3.71 (s , 3 Η) 2 58 2.80 (m, 3 H) 2.02 (s, 3 H) 1.96-2.00 (m, 1H). Example U4 N2-(4-(4-Chloro-1Η-imidazole-i-yl)_3_methoxyphenyl)_N4_(5, isopropyl-2-methylphenylphenyl-6,7 dihydrogen _5H cyclopenta[pyrimidine 4 diamine

2-Hydroxy-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (preparation Gp) (26.0 mg, 1 〇〇μιη〇1) Adding Dou Xingxin Chlorine "Indazole-Ibu" to a solution of dioxane (ratio: i, volume: 175 μΐ)_3_decyloxybenamine (Preparation A) (22.37 mg, 1 〇〇μηιοί And AcOH (ratio: 1.000 'volume: 175 μΐ). The resulting mixture was brought to 1 Torr. and the mixture was stirred overnight. The reaction mixture was brought to pH 1 添加 by adding 1 N aqueous NaOH. EtOAc (3×4 mL The resulting mixture was extracted. The combined organic extracts were washed with brine (4 mL) EtOAc EtOAc EtOAc EtOAc ) +=565·2. Examples 215Α and 215Β 4-(4-(5-isopropyl-2-methylphenylamino) stupyl-6J-di-argon_5Η•cyclopenta[d]cycline_ 2_ylamino)benzonitrile 149653.doc -567· 201107311

The 4-aminobenzonitrile was combined with the preparation Gp using the method of Example 214 to give the title compound in two different and separable abbreviated isomers. LC-MS (Μ+Η)+=460·3. Examples 216-256 The appropriate aniline was joined to the preparation Ga using the following general procedure. Coupling Method Aa: This method is as described in Example 8. Coupling method Ba: The two components were heated in 1:1 HOAc/dioxane at 100 °C. Analyze on the following column:

LC method Ab : Phenomenex Luna 3x50 95/5 to 5/95 water / MeOH, 0.1% TFA LC Method Bb : Phenomenex Luna 2x50 95/5 to 5/95 water / CH3CN, 0.1% NH4OAc

LC method Cb: Phenomenex Luna 2x50 95/5 to 5/95 water/MeOH, 0.1% TFA LC Method Db: Waters 2x50 95/5 to 5/95 Water/MeOH, 0.1% NH4〇Ac LC Method Eb: Supelco Ascentis Exp 95/5 to 5/95 water/CH3CN, 0.1% NH4OAc reports the LC residence time e and the gradient duration (rt/grt). 149653.doc - 568- 201107311

EXAMPLES Compound Name Coupling Method 3 LC Method b LC Retention Time e (M+H) + 216 N4-Mercapto-N2-(2-amidinopyridin-4-yl)-7-phenyl-6,7-dihydrogen -5H-cyclopenta[d]pyrimidine-2,4-diamine BA 1.77/3 332.2 217 N2-(3-methoxyphenyl)-N4-indolyl-7-phenyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidine-2,4-diamine AD 3.63/4 347.2 218 N2-(4-fluorophenyl)-N4-methyl-7-phenyl-6,7-dihydrogen -5H-cyclopenta[d]pyrimidine-2,4-diamine AD 3.68/4 335.2 219 N2-(3,5-difluorophenyl)-N4-indolyl-7-phenyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AD 3.87/4 353.2 220 N2-(4-Ga-3-methoxyphenyl)-N4-methyl-7-phenyl -6,7-dihydro-5H-cycloindolo[d]pyrimidine-2,4-diamine AD 3.83/4 381.2 221 N2-(4-bromo-2-indolylphenyl)-N4-indenyl -7-phenyl-6,7-diaza-5H-cycloindolo[d]pyrimidine-2,4-diamine AD 4.10/4 425.1 222 N2-(4-fluoro-3-methoxyphenyl) -N4-methyl-7-phenyl-6,7-di-r-511-3⁄4戍弁[d]pyrimidine-2,4-diamine AD 3.63/4 365.2 223 N4-methyl-7-phenyl- N2-(pyrimidin-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AD 3.12/4 319.2 224 N4-mercapto-7-phenyl-N2 -(pyridin-4-yl)-6, 7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AD 2.85/4 318.2 225 4-(4-(曱月安基)-7-phenyl-6,7-二风-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile AD 3.57/4 342.2 226 4-(4-(decylamino)-7-phenyl-6,7-di-mouse _ 5H -cyclopenta[d]pyrimidin-2-ylamino)benzonitrile AC 2.94/4 342.1 149653.doc -569- 201107311 Example Compound Name Coupling Method 3 LC Method b LC retention time. (M+H)+ 227 4-(4-(methylamino)-7-phenyl-6,7-diaza-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile 2.92/4 342.1 228 2-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile AE 2.64/ 8 342.2 229 4-(4-(decylamino)-7-phenyl-6,7-diaza-5H-cyclopenta[d]pyrimidin-2-ylamino)-1-naphthalenecarbonitrile AE 5.73 /8 392.2 230 5-(4-(Methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)2-cyano AE 4.54/8 343.2 231 2-(4-(4-(Amino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl Acetonitrile AE 4.65/8 356.2 232 2-(4-(Methylamino)-7-phenyl-6,7-diaza-5H-cyclopenta[d]pyrimidin-2-ylamino)-1H- Benzo[d]imidazol-5-indolecarbonitrile AE 4.57/8 382.2 233 3-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2-ylamino)benzonitrile BE 4.37/8 342.1 234 N2-(4-Terbutylphenyl)-N4-indolyl-7-phenyl-6,7-dihydro-5H-cyclopenta [d] Pyrimidine-2,4-diamine BE 5.47/8 373.2 235 N4-mercapto-N2-(4-(methylsulfonyl)phenyl&gt;7-phenyl-6,7-dihydro-5H -cyclopenta[d]pyrimidine-2,4-diamine BE 3.79/8 395.1 2 36 N4-mercapto-7-phenyl-N2-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine BE 5.13/8 400.8 237 4-(4-(decyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phthalamide BE 4.47/8 367.2 238 4-(4-(decylamino)-7-phenyl-6,7-diaza-5H-cyclopenta[d]pyrimidin-2-ylamino)-2-(III Fluorinyl)benzonitrile BE 4.90/8 410.1 149653.doc • 570· 201107311

Example Compound Name Coupling Method 3 LC Method b LC Retention Time e (M+H) + 239 N4-Methyl-7-phenyl-N2-(4-(trifluoromethyl)phenyl)-6,7-II Hydrogen-5H-cyclopenta[d]pyrimidine-2,4-diamine BE 5.13/8 385.1 240 5-(4-(methylamino)-7-phenyl-6,7-di lL-5H-ring Pentative [d]pyrimidin-2-ylamino)-2,3-dihydro-111-inden-1-one BE 3.89/8 371.2 241 2-(4-(methylamino)-7-phenyl- 6,7-dihydro-5H-cyclopenta[d]pyridin-2-ylamino)-1imidazole-4,5-dicarbonitrile BE 4.08/8 357.2 242 2-&gt;Smelly-5- (4-(Methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile BE 4.89/8 420.1 243 N,N-II Methyl-4-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzimidamide BE 3.50/8 388.2 244 1-(4-(4-(Amidino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)cyclopentane Nitrile BE 4.91/8 410.2 245 N4-Methyl-7-phenyl-N2-(l,2,3,4-tetradentium-iso-[-6-yl)-6,7-di^-5H- ring Pentative [d]pyrimidine-2,4-diamine BE 4.14/8 372.2 246 4-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidin-2-ylamino)-2-(trifluoromethoxy) Benzoquinone BE 5.04/8 426.1 247 1-(4-(4-(indenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamine Phenyl)cyclopropanecarbonitrile BC 3.30/4 382.3 248 1-(2-decyloxy-4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclo Pentative [d]pyrimidin-2-ylamino)phenylamino)cyclopropanecarbonitrile BC 3.06/4 427.1 249 N4-methyl-N2-(2-methyl-1H-indol-5-yl) -7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AB 1.75/2 370.3 149653.doc -571 - 201107311 Example compound name coupling method 3 LC method b LC retention time e (M+H)+ 250 N2-(benzofuran-5-yl)-N4-mercapto-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine AB 1.85/2 357.2 251 N2-(1H-indol-5-yl)-N4-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidine-2,4-diamine AB 1.68/2 356.3 252 N4-mercapto-N2-(2-mercaptobenzo[d]oxazole-6-yl)-7-phenyl-6,7-dihydro -5H-cyclopenta[d]pyrimidine-2,4-diamine AB 1.73/2 372.3 253 N2-(1H-benzo[d]imidazol-6-yl)-N4-indolyl-7-phenyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AB 1.47/2 357.2 254 N4-mercapto-N2-(l-fluorenyl-1H-indol-5-yl -7-stupyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AB 1.82/2 370.3 255 N4-mercapto-N2-(2-mercaptobenzophenone) [d]thiazol-6-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AB 1.78/2 388.2 256 N2-(4-bromo -3-decyloxyphenyl)-N4-mercapto-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine AA 2.63/4 425.0/ 427.0 Coupling Method Aa: This method is as described in Example 8. Coupling method Ba: The two components were heated in 1:1 HOAc/dioxane at 100 °C. Analysis was performed on one of the following columns 5: LC method Ab : Phenomenex Luna 3x50 95/5 to 5/95 water / MeOH,

0.1% TFA LC Method Bb: Phenomenex Luna 2x50 95/5 to 5/95 Water/CH3CN, 0.1% NH4〇Ac LC Method Cb: Phenomenex Luna 2x50 95/5 to 5/95 water/MeOH, 149653.doc • 572 · 201107311

0.1% TFA LC Method Db: Waters 2χ50 95/5 to 5/95 Water/MeOH, 0.1% NH4OAc LC Method Eb: Supelco Ascentis Exp 95/5 to 5/95 Water/CH3CN, 0.1% NH4〇Ac Reported LC retention time c and gradient duration (rt/grt). Example 25Ί 1-(4-(4-(Methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone oxime HN〆

Example 25 6 (20 mg, 0.047 mmol), tributyl(1-ethoxyethenyl)tin (67.9 mg, 0.188 mmol) and hydrazine (5.43 mg, 4.70 μηιοί) in toluene (188 μΐ^) The mixture was heated at 8 ° C for 12 hours. The crude product was purified by preparative HPLC. The obtained product was treated with HCl (.sup.8 eq.) of acetone (0.285 M) and stirred at room temperature overnight. The mixture was concentrated and washed with EtOAc &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&& 5H-Cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone (4 mg, 10.3 μηιοί, yield 22%). LC-MS (Μ+Η)+= 389.2. NMR (500 MHz, MeOD) δ ppm 7.74 (d, "7-8.55 Hz, 1 Η) 7.66 (s,1 Η) 7.36-7.49 (m,3 Η) 7.19-7.36 (m, 2 H) 7.08 (dd , 7=8.55, 1.83 Hz, 1 H) 4.45 (br. s., 1 H) 3.86-3.98 (m, 3 H) 3.16-3.24 (m, 3 H) 2.93 (br. s., 149653.doc . 573 . 201107311 1 Η) 2.73-2.86 (m5 2 Η) 2.53-2.63 (m, 3 Η) 2.11-2.23 (m, 1 Η). Example 258 ^2-(4-Cyclopropylphenyl)-7-(4-fluorophenyl)-}^4-methyl-6,7-dihydro-511-cyclopenta[d]pyrimidine-2 4-diamine

To a solution of the fluorinated analog of Example 256 (150 mg, 0.338 mmol) in toluene (ratio: 20, volume: 1611 μΐ) was added cyclopropyl-flunic acid (37.8 mg, 0.440 mmol), PdOAc2 (3.80 mg) , 0.017 mmol), tricyclohexylphosphine (9.49 mg, 0.034 mmol), potassium orthophosphate (251 mg, 1.184 mmol) and water (ratio: 1.000, volume: 81 μΐ). The resulting mixture was brought to ll 〇 ° C and stirred overnight. The reaction mixture was diluted with EtOAc EtOAc m. Purification by flash chromatography (cerium oxide, EtOAc/hexanes) afforded N2-(4-cyclopropyl-3-decyloxyphenyl)-7-(4-fluorophenyl)-indole 4-indole The -6,7-dihydro-5 oxime-cyclopenta[d] was squirted with 2,4-diamine (15 mg, 0.037 mmol, yield 10.96%). LC-MS (Μ+Η)+=405·1. NMR (500 MHz, MeOD) δ ppm 7.60 (d, J = 1.83 Hz, 1 H) 7.19 (dd, J = 7.93, 5.80 Hz, 2 H) 6.97-7.14 (m, 3 H) 6.69-6.78 (m, 1H) 4.05-4.22 (m, 2 H) 3.62-3.71 (m, 3 H) 2.98-3.11 (m, 3 H) 2.72-2.85 (m5 1 H) 2.55-2.72 (m, 2 H) 1.90-2.05 ( m, 2 H) 149653.doc •574· 201107311 1.26 (t, /=7.17 Hz, 1 H) 0.73-0.86 (m, 1 H) 0.46-0.61 (m, 1 H). Example 259 N2-(4-ethynylphenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-di amine

Tributyl(ethynyl)stannane (53 ·3 mg, 0.169 mmol), fluorinated analog of Example 256 (50 mg, 0.113 mmol) and hydrazine (10.0 mg, 0.011 mmol) in toluene (226 μM) The mixture was heated at 110 ° C for 2 hours. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to give N2-(4-ethynyl-3-methoxyphenyl)-7-(4- Fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]n-densidine- 2,4-diamine (1.5111 L,3.8601]1〇1).1^( 3· MS (M+H)+=389.2 ° !H NMR (500 MHz, chloroform-d) δ ppm 7.86 (s, 1 H) 7.31 (d, 7=8.55 Hz, 2 H) 7.16 (dd, 7= 7.78, 5.65 Hz, 3 H) 7.01 (t, /=8.70 Hz, 2 H) 6.71 (br. s., 1 H) 4.52 (br. s., 1 H) 3.71 (s, 3 H) 3.15 (d , J = 4.88 Hz, 3 H) 2.67 (d, J = 9.77 Hz, 3 H) 1.95-2.14 (m, 1 H).

Example 26Q 7-(4-Fluorophenyl)-N4-methyl-N2-(4-(prop-l-alkynyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2,4-diamine 149653.doc • 575- 201107311

Dibutyl(prop-1-ynyl)tin (55.7 mg, 0.169 mmol), the fluorinated analog of Example 256 (5 〇, 0.113 mmol) and hydrazine (10.0 mg, 0.011 mmol) in toluene ( The mixture in 226 μί) was heated under u〇〇c for 2 hours' then the solvent was removed in vacuo. Purification of the residue by preparative HPLC gave 7-(4-fluorophenyl)-N2-(3-methoxy-4-(prop-1-ynyl)phenyl)-N4-indolyl-6, 7-Dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (2.0 mg, 4.97 μηιοί). LC-MS (M+H)+ = 403.3. 'H NMR (400 MHz, gas-c〇δ ppm 7.80 (d, "7=1.76 Hz, 1 Η) 7.10-7.23 (m,3 Η) 6.93-7.08 (m, 2 H) 6.73 (s, 1 H) 4.51 (br. s., 1 H) 4.05-4.29 (m, 1 H) 3.70 (s, 3 H) 3.14 (d, J=4.77 Hz, 3 H) 2.56-2.79 (m,3 H) 2.09 - 2.14 (m, 3 H) 1.99-2.09 (m, 1 H). Example 261 N2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-N4-methyl -7-phenyl-6,7-dihydro-5 H-cyclopenta[d]carcinoma bite-2,4-diamine

Will 2-methyl. 00-4-phenylphosphonate (25 · 1 mg, 0·1 83 mmol), Example 256 (26 mg, 0.061 mmol), hydrazine (14.1 mg, 0.012 mmol) and sodium carbonate (13.0 mg, 0·) 122 mmol) in Benzene (255 μ! 〇 / water (149 653.doc • 576 · 201107311 in 50 μΙ〇, heating at 150 ° C for 5 hours) and then removing the solvent in vacuo. Purification of the residue by preparative HPLC ''N-(3-methoxy-4-(2-methyl 0-pyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6,7·dihydro-5H- Cyclopenta[d]pyrimidine-2,4-diamine (5.0 mg, 0.011 mmol). LC-MS (M+H)+=438.2.H NMR (500 MHz, MeOD) δ ppm 8.60 (br. s .. 1 H) 8.06- 8.19 (m, 2 H) 7.75 (d, /=1.83 Hz, 1 H) 7.60-7.70 (m, 1 H) 7.38-7.49 (m, 2 H) 7.22-7.38 (m, 4 H) 4.43-4.57 (m, 1 H) 3.86-3.99 (m, 3 H) 3.17-3.26 (m, 3 H) 2.89-3.01 (m, 1 H) 2.73-2.89 (m,5 H) 2.19 ( Dt, /=9.16, 6.87 Hz, 1 H). Example 262 m-(3-methoxy-4-(.pyridin-4-yl)phenyl)-N4-methyl-7-phenyl-6 ,7-Dihydro-5}{-cyclopenta[(1]°Bite-2,4-diamine

4-(tributyltinyl) ruthenium ratio (69.2 mg, 0-1 88 mmol), Example 256 (20 mg, 0.047 mmol) and hydrazine (5.43 mg, 4.70 μιηοΐ) in benzene (196 μ!〇/ The mixture of water (39 μΙ〇 was heated at 10 ° C for 12 hours, then the solvent was removed in vacuo. The residue was purified by preparative HPLC to afford N2-(3-methoxy-4-(pyridine) 4-yl)phenyl)-N4-mercapto-7-phenyl-6,7-dihydro-5H-cyclopenta[d] ton. 1,2,4-diamine (4. 〇1^, 9.440111〇1).1^-MS (Μ+Η)+=424·2. NMR (500 MHz, MeOD) δ ppm 8.20-8.90 (m, 4H) 7.74 (d, J=1.83 Hz, 1 H) 7.62 -7.70 (m, 1 H) 7.39-7.47 (m, 2 H) 7.23-7.37 (m, 4 H) 4.43-4.54 (m, 1 149653.doc • 577 · 201107311 Η) 3.94 (s, 3 Η) 3.22 (s, 3 Η) 2.89-3.01 (m, 1 Η) 2.75-2.87 (m, 2 Η) 2.12-2.29 (m,1 Η). Example 263 Ν2-(3· ψoxy-4-(pyridine- 3-yl)phenyl)-indole 4-methyl-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine

a mixture of 3-(tributylstannyl)pyridine (55.4 mg, 0.150 mmol), Example 256 (16 mg, 0.061 mmol) and hydrazine (4.35 mg, 3.76 μιηο) in toluene (188 μΙ〇 at 100 ° C) Heating for 12 hours, then removing the solvent in vacuo. The residue was purified by preparative HPLC to give N2-(3- methoxy-4-(.pyridin-3-yl)phenyl)-N4-indolyl- 7-Phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (4.0 mg, 9.44 μηιοί). LC-MS (M+H)+= 424.2. 500 MHz, MeOD) δ ppm 8.52 (br. s., 2 Η) 7.67-7.76 (m, 2 H) 7.55-7.64 (m, 1 H) 7.43-7.50 (m, 1 H) 7.41 (d, J= 7.32 Hz, 2 H) 7.32-7.37 (m, 1 H) 7.17-7.31 (m, 3 H) 4.41-4.56 (m, 1 H) 3.88 (s, 3 H) 3.16-3.28 (m, 3 H) 2.88 -3.02 (m,1 H) 2.73-2.88 (m,2 H) 2.09-2.26 (m,1 H). Biological methods inhibit the production of Aβ 1 - 4 0 and Αβ 1 - 42 by 1:20 The division was performed twice a week, and the Η4 cells (H4 APP751 SWE pure 8.20, BMS developed) stably transfected with Swallow mutation containing Swedish mutation were maintained in the logarithmic growth phase. 149653.doc -578- 201107 311 Determine IC5. Apply 30 μL of cells (1.5 x 10 4 cells/well) in DMEM medium containing 0.0125% BSA (Sigma A8412) directly to a 384-well compound dish containing 0.1 μM serially diluted compound in DMSO (Costar) 3709). After incubation for 19 hours at 5 ° C. in CO 2 at 37 ° C, the plate was briefly centrifuged (1 rpm, 5 minutes). Transfer 10 μ ΐ aliquots from each well to the second The assay plate (Costar 3 709) was used for Αβ40 measurement. The antibody mixture was freshly prepared by dilution with 40 mM Tris-HCl (pH 7.4) containing 0.2% BSA and added to the assay plate. An antibody specific for the Αβ42 new epitope (565, BMS development; binding to Wallac reagent (Perkin Elmer)) and Αβ peptide Ν terminal sequence (26D6, SIBIA development; with APC (Perkin Elmer) The cells were mixed and 20 μM of the mixture was added to each well of the cell plate so that the final concentration of 565 was 0.8 Ng/well and the final concentration of 26 D6 was 75 Ng/well. To measure Αβ40, an antibody specific for the Αβ40 novel epitope (TSD, BMS development; combined with Walker reagent (Perkin Elmer)) was mixed with 26D6 as described above, and 20 μM mixture was added to the pre-cell culture. The 10 μΐ aliquot of the disc was removed so that the final concentration of TSD was 1.6 Ng/well and the final concentration of 26D6 was 17.5 Ng/well. The test plates containing the antibodies were sealed with aluminum foil and incubated overnight at 4 °C. Signals were measured using a Viewlux counter (Perkin Elmer) and the CurveMaster (based on Excel Fit) curve fit was used to determine IC5 enthalpy. Table 1 (below) illustrates the activity of representative compounds of the invention based on IC50 values of Αβ42 cells in H4 APP751 SWE pure line 8.20. 149653.doc - 579- 201107311 Table 1 Example Compound Activity Grade 3 Example Compound Activity Level 3 1 +++ 85 Ten + 2 +++ 86 ++ 3 87 60 nM 3A +++ 88 ++ 3B ++ 88A 4.5 nM 4 +++ 88B ++ 4A -HH- 89 ++ 4B ++ 90A ++ 5 +-H- 90B 270 nM 5A +++ 91A +++ 5B ++ 91B + 6 ++ 92 ++ 6A + ++ 93 20 nM 6B -H- 94 +++ 7A +++ 94A +++ 7B ++ 94B ++ 8 +++ 95 +++ 9 8.1 nM 95A +++' 10 +++ 95B ++ 11 +++ 96 +++ 11A 3.8 96A +++ 11B +++ 96B 4.6 nM 12 +++ 97 +++ 12A +++ 97A +++ 13 . 97B ++ 14 98 ++ 15 ++ 98A +++ 16 -Η- 98B ++ 16A +++ 99 19 nM 16B + 99A ++ 17 ++ 99B 190 nM 17A 120 nM 100 +++

149653.doc - 580- 201107311

Example Compound Activity Grade 3 Example Compound Activity Grade 3 17B ++ 100A 4.7 nM 18 ++ 100B ++ 18A 8.8 nM 101 ++ 18B ++ 101A +++ 19 ++ 101B ++ 19A ++ 102 +++ 19B 59 nM 102 A +++ 20 +++ 102B ++ 20A +++ 103 ++10 20B ++ 103A +++ 21 ++ 103B ++ 21A ++ 104 ++ 21B + 105 8.8 nM 23 ++ 106 + + 23A ++ 107 ++ 23B + 107 A ++ 24 ++ 107B + 24A ++ 108 20 nM 24B 200 nM 109 A +++ 25 ++ 109B +-H* 26 +-H- 110A 26A ++ 110B ++ 26B ++ 111 35 nM 27 ++ 112 -H-+ 28 ++ 112A +++ 28A ++ 112B ++ 29 ++ 113 5.7 nM 29A ++ 113A +++ 29B ++ 113B ++ 30 + + 114 +++ 30A ++ 114A ++ 30B 230 nM 114B + 31 + 115 32 ++ 115A 149653.doc -581 - 201107311 Example Compound Activity Grade 3 Example Compound Activity Grade 3 33 100 nM 115B ++ 34 ++ 116 ++ 35 +++ 116A +++ 36 ++ 116B + 37 +++ 117 45 nM 38 ++ 117A ++ 38A 12 nM 117B + 38B ++ 118 ++ 39 ++ 118A +++ 39B + 118B + 40A +++ 119 ++ 40B + 119A 7.4 nM 41 ++ 119B + 41A 120 ++ 41B ++ 120A +++ 41C ++ 120B + 41D ++ 121 ++ 42 ++ 121A +++ 42A ++ + 121B 120 nM 43 +++ 122 A +++ 44 13 nM 123A ++ 44A 123B 370 nM 45A ++ 124 ++ 45B 2.5 nM 124 A +++ 45C ++ 124B ++ 45D +++ 125 ++ 46 +++ 126 ++ 46A +++ 127 ++ 46B ++ 127 A 47 +++ 127B ++ 48 18 nM 128 + 48A -hH- 129 ++ 48B 130 nM 129 A +++ 49 +++ 130 +++

149653.doc - 582 - 201107311

Example Compound Activity Grade 3 Example Compound Activity Grade 3 49A +++ 130Α +++ 49B ++ 131 ++ 50 +++ 131Α +++ 50A +++ 132 -H- 50B ++ 132Α 15nM 51 4.5 nM 133 + + 51A +++ 133Α +++ 51B +++ 134 +++ 52 ++ 134Α 3.6 nM 52A +++ 135 -Η- 52B ++ 135Α ++ 53 -Η- 136 +-Η- 53A +++ 136Α -Η-+ 53B ++ 137 11 nM 54 ++ 137Α +++ 54A ++ 138 ++ 54B 138Α +++ 55 ++ 139 ++ 55B ++ 139Α ++ 56 ++ 140 -Η- 56A + ++ 140 A 56B Ή- 141 ++ 57A 14ηΜ 141A +++ 57B + 142 ++ 58A +++ 143 ++ 58B 120 nM 143B 430 nM 59 ++ 144 ++ 59A +++ 144B 540 nM 60 ++ + 145 ++ 60A 5.6 nM 146 ++ 60B ++ 147 ++ 61 -Η- 148A +-H- 61A +++ 149 ++ 61B ++ 150 ++ 149653.doc • 583 - 201107311

Example Compound Activity Grade 3 Example Compound Activity Grade 3 62 ++ 151 +++ 62A +++ 151Α +++ 62B 86 nM 152 ++ 63 ++ 153 ++ 63A ++ 154 ++ 63B + 154Α +++ 64 ++ 155Α +++ 64A +++ 156 +++ 64B ++ 156Α 9.8 nM 65 ++ 157 ++ 65A 5.3 nM 157Α ++ 65B 160 nM 158 ++ 66 ++ 159 10+ 66A + 160 ++ 66B +++ 161 + 67 -Η- 162 ++ 67A -Η- 162 A ++ 67B 540 ηΜ 163Α +++ 68 ++ 164 A ++ 69 165 ++ 69A +-Η- 165 A ++ 69B + 165B 180 nM 70 ' +++ 166 + 70A +++ 167 A 26 nM 70B ++ 168A +++ 71 ++ 169 ++ 71A +++ 169A +++ 71B ++ 170 ++ 72 +++ 170A + ++ 73 3.8 ηΜ 171 16nM 74A ++ 171A ++ 75 ++ 172 A +++ 75A +++ 172B + 75B ++ 173 490 nM 149653.doc •584· 201107311

Example Compound Activity Grade 3 Example Compound Activity Grade 3 76 ++ 174 ++ 77 ++ 175 ++ 78 175 A +++ 78A 19nM 176 +++ 78B ++ 176A +++ 79A 5.8 nM 176B +++ 79B + + 177 ++ 80 ++ 178 +++ 80A ++ 179 ++ 81 ++ 180 ++ 82 ++ 181 ++ 82A +++ 181A +++ 82B ++ 181B 50 nM 83 ++ 182 ++ 83A +++ 182A +++ 83B ++ 182B ++ 84 ++ 183 11 nM 84A ++ 183A +++ 84B 290 nM 183B ++ 184 ++ 211 +++ 185 ++ 212 33 nM 186 ++ 213 insol 187 ++ 214 77 nM 187A ++ 215A Λ 187B ++ 215B 173 nM 188 19nM 216 A 189 +++ 217 Λ 189A •f++ 218 3700 nM 189B ++ 219 Λ 190 37 nM 220 550 nM 191 ++ 221 Λ 191A ++ 222 Λ 191B 96 nM 223 ΙΙΟΟΟηΜ 192 64 nM 224 Λ 149653.doc -585 · 201107311 Example Compound Activity Grade 3 Example Compound Activity Level 3 192 A 170 nM 225 18 nM 192B 16 nM 226 + 193 ++ 193B ++ 193 A + 227 12 nM 194 ++ 228 194 194A ++ 229 Λ 194B 175 nM 230 42 nM 195 17 nM 231 + 195A 26 nM 232 Λ 195B + 233 Λ 196 ++ 234 Λ 196 A -H-+ 235 + 196B 54 nM 236 Λ 197 16 nM 237 29 ηΜ 197A 60 nM 238 + 197B +++ 239 + 198 ++ 240 Insol 198A + 241 Insol 198B 15nM 242 67 nM 199 ++ 243 + 199 A + 244 Λ 199B +-H- 245 Λ 200 ++ 246 31 ηΜ 200A + + 247 + 200B ++ 248 Λ 201 5.3 nM 249 Λ 201A 10 nM 250 Λ 201B ++ 251 Λ 202 +++ 252 Λ 203 19nM 253 5900 ηΜ 203A +++ 254 1000 ηΜ 203B ++ 255 Λ 204 19 nM 256 97 ηΜ 204A 19 nM 257 ++ 149653.doc • 586· 201107311 Example Compound Activity Grade 3 Example Compound Activity Level a 204Β + 258 Λ 205 ++ 259 940 ηΜ 206 15ηΜ 260 860 ηΜ 207 + 261 +++ 208 ++ 262 +++ 209 +++ 263 32 ηΜ 210 61 ηΜ 3 activity is based on the IC50 value of Αβ42 cells in H4APP751 SWE pure line 8.20.

+++ = 1.5 nM-0.0099M

++ = 0.010-0.100 μΜ + = 0.100-1.0 μΜ Λ = &gt; 1.0 μΜ It should be apparent to those skilled in the art that the present invention is not limited to the foregoing illustrative examples, and that it may be Specific form of implementation. Accordingly, the present invention is to be considered in all respects as illustrative and not limiting, and the scope of the accompanying claims It is encompassed by the present invention. 149653.doc 587 -

Claims (1)

201107311 VII, the scope of application for patents: 1- a compound of formula (I), A, % Wherein &quot;Haihefang ring condition is 1 or 2 selected from halo or its pharmaceutically acceptable salt A is 1 to 3 independently selected 6 member heteroaryl ring halogen CN6 alkyl, perylene, amine Substituent; (I) 'The group of 5 or Cl-6 alkoxy which is a hetero atom of nitrogen, oxygen and sulfur and the group B of a C, -6 alkyl group are selected from phenyl and <. The base is where the phenyl group is. Substituted by one or two substituents independently selected from the group consisting of: c 1 ·6 alkoxy, C!·6 leucoyl, Cw-indenyl-C!·6 alkoxy, cyanide a group, a Cl-3 dialkylamino alkoxy group, a halogen group, a halogen CK6 alkoxy group, a halogen Ci. 6 alkyl group, a hydroxyl group, a methylamino group and an amine group; 149653.doc 201107311 Rb • Rd Λ ” indicates the point of attachment to the nitrogen atom of the parent molecule; plant ～ indicates the point of attachment to the Ε moiety; R is selected from the group consisting of hydrogen, Cw alkyl, 〇2·6 alkenyl and hydroxyl; R is - NRxRy 'wherein Rx and R/ are independently selected from hydrogen, Cl_4 alkoxy Cl-4 alkoxy Cw alkyl, Cw alkoxycarbonyl, (^-6 alkyl, C3.7 cyclod, (C3·7) a cycloalkyl)ci.4 alkyl group, a hydroxy Cm alkyl group, and a trimethylidene group wherein the alkyl portion of the (Cw cycloalkyl) CK4 alkyl group may be optionally substituted by a C alkyl group; or Rx and V, together with the nitrogen atom to which it is attached, forms a 4 to 7 membered monocyclic or bicyclic ring, optionally containing a double bond and optionally a heteroatom selected from the group consisting of ruthenium, NR/ and S; wherein the rz is selected from the group consisting of hydrogen and Ci- 6 alkyl and Cw alkoxycarbonyl; wherein the ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of Cu6 alkoxy, C..6 alkyl, halo, halogen C-4 alkyl , thiol, -NRfRg, pendant oxy (οχο), spirodioxanthyl; wherein the Rg is independently selected from the group consisting of hydrogen, Cm alkoxycarbonyl, and C1-6Hyun&gt; From hydrogen, Cw alkylsulfonyl, Cw alkyl Sulfonamide, amine group, Ci-6 alkylamino group, Ci.6 dialkylamino group, C3-7 ring-based amine group, hydroxyl group and C!.4 alkoxy group; Rd is selected from hydrogen, Cw alkyl, Ci.4 alkoxy Cm alkylcarbonyl, CN6 alkoxycarbonyl, Cm alkylcarbonyl, Cw alkylsulfonyl, C3-7 cycloalkylsulfonyl, C3-7 cycloalkylcarbonyl, Cw Alkylamino Cw alkylcarbonyl 149653.doc 201107311 and a halogen Cm alkyl group, wherein the alkoxycarbonyl group, the alkylcarbonyl group and the alkyl moiety of the alkylsulfonyl group are optionally selected from Ci 4 dioxane Substituted with a substituent of a arylamino group and a Cw alkoxy group; and the E group is selected from the group consisting of Cw alkyl group, C4-6 cycloalkyl group, (c47 cycloalkyl)Ci4 alkyl group, phenyl fluorenyl group, phenyl group and containing hydrazine or 2 a 5- to 6-membered heteroaryl ring of a nitrogen atom, wherein the phenyl moiety of the indolyl group, the indoleyl group, and the heteroaryl ring are each independently selected from the group consisting of 1, 1 or 3 independently selected from the group consisting of Cl. Substituted by a substituent of a Ci 6 alkoxy group, a cyano group, a halogen group, a dentate Cm alkoxy group, and a halogen Cw alkyl group. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a a 5-membered heteroaryl ring containing 1 to 3 nitrogen atoms; wherein the heteroaryl ring is as appropriate In the case of a compound selected from the group consisting of _ group and C!.1 alkyl group. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the B system is derived from a stupid base and a η ratio. a phenyl group, wherein the phenyl group is substituted by a substituent or a substituent independently selected from the group consisting of cw alkoxy groups and a functional group. 4. The compound of claim 3, or a pharmaceutically acceptable compound thereof a salt thereof, wherein E is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of Cl_1 alkyl, Ci 6 alkoxy, cyano, dentyl, Cw alkoxy and Cy alkyl Stupid. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of ~ The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein 201107311 R is a collar Ry, wherein RX&amp;Ry is independently selected from hydrogen, Cw alkoxy C. The alkyl moiety of the group, c丨·6 alkyl group, Cw cycloalkyl group, hydroxy C 4 alkyl group and triterpene “C3·7 cycloalkyl group” Ci·4 alkyl group may be hydrogenated by Ci·4 as the case may be. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Rb is -NW, the towel my and its attached nitrogen atom form a 4 to 7 member mono- or bicyclic ring, optionally containing one And other heteroatoms of nrz, wherein the RZ is selected from the group consisting of Ci. 6 alkyl and C, -4 alkoxycarbonyl; wherein the coating is substituted with 1 or 2 substituents independently selected from the group consisting of: 6 alkane Oxyl, CU6 alkyl, halo, halo*alkyl, hydroxy, _NRfRg, pendant oxy and spiro dioxolanyl; wherein Rf&amp;Rg is independently selected from nitrogen, c..4 alkoxycarbonyl And a compound of the formula 4, or a pharmaceutically acceptable salt thereof, wherein the D is selected from the group consisting of 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R is -NRxRy, wherein the sigma* and Ry are independently selected from hydrogen, d4 alkoxyl-4 alkyl, C丨·6 alkyl, C3·7 ring-form, hydroxyl c丨_4 alkyl and triterpene, wherein the alkyl moiety of the (匸3·7 cycloalkyl)Ci_4 alkyl can be obtained by C 〖 4 alkoxy substituted. 10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Rb is -NW, which allows RX&amp;Ry to form together with its attached nitrogen atom. 4 149653.doc 201107311 to 7 member single or double ring And optionally, other heteroatoms selected from the group consisting of ruthenium and NRZ; wherein Rz is selected from the group consisting of Cl-6 alkyl and Ci-4 alkoxycarbonyl; wherein the cyclic is optionally substituted with 1 or 2 substituents independently selected from: c 1 6 alkoxy, C. 6 alkyl, halo, halo Cm alkyl, hydroxy, _NRfRg, pendant oxy and spiro dioxolanyl; wherein "and Rg are independently selected from hydrogen, Cw alkoxy A carbonyl group and a C 6 alkyl group. 11. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R^-NW, wherein R4Ry is independently selected from the group consisting of hydrogen, c"4 hospitaloxy C!-4 alkyl, Ci-6 alkyl 'C3.7 cycloalkyl, hydroxy Cw alkyl and triterpenoid The methyl group of the (Cp cycloalkyl) C!·4 alkyl group can be seen by the way! • 4 alkoxy substitution. 13. A compound according to the &amp; ocular compound, or a pharmaceutically acceptable salt thereof, wherein m-NW '#mRy forms a nitrogen atom with its attached __* to 7 members of the early or bicyclic ring, optionally containing one Other heteroatoms selected from the group consisting of ruthenium and nrz; wherein the Rz is selected from the group consisting of Cl.6 alkyl and Ci4 aerobic base; the soil is optionally substituted by U2 substituents independently selected from the group consisting of: c" alkoxy a group, a "alkyl group, a functional group", a Ci4 alkyl group, a thiol group, an oxo group, and a spirocyclodioxol group; wherein R and Rg are independently selected from the group consisting of wind, Cl-4, oxycarbonyl and c _6 alkyl. 149653.doc 201107311 14. A compound selected from the group consisting of N2-(3-decyloxy-4-(3-indolyl-1H-1,2,4-triazole-1) -yl)phenyl)-N4 methyl-7-benyl-6,7-indol-5H-cyclopenta(CyCi〇penta)[d] guanidine-2,4-diamine; N2-( 3_|t-4-(3-methyl-1H-1,2,4-tris-sodium)phenyl)·ν4-methyl-7-phenyl-6,7-dihydro-5Η- Cyclopenta[d]pyrimidine_2,4-diamine; N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazolyl)phenyl)_N4_indolyl-7- Phenyl-6,7-dihydro-5H-cyclopenta[d]saponin_2,4-diamine; N2-(3-fluoro-4-(5) -mercapto-1H-1,2,4-triazole_!_yl)phenyl)·ν4-mercapto-7-phenyl-6,7-dihydro-5Η-cyclopenta[(1] spray 2,2-diamine; Ν2-(3-fluoro-4-(5-fluorenyl-1Η-1,2,4-triazol-1-yl)phenyl)_ν4-indolyl-7-phenyl -6,7-dihydro-511-cyclopentanyl[(1]11-biti-2,4-diamine; Ν2-(4-(4-气-1Η-imidazol-1-yl)-3-曱Oxyphenyl)-Ν4,Ν4_dimethyl-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine; (S)-N2-(4 -(4- gas-1 Η-imidazol-1-yl)-3-methoxyphenyl)-indole 4, fluorenyl 4-dimercapto-7-phenyl-6,7-dihydro-5 fluorene-cyclopenta[ d]pyrimidine-2,4-diamine; (R)-N2-(4-(4-Galy-1Η-imidazol-1-yl)-3-decyloxyphenyl)-indole 4, indole 4-didecyl -7-phenyl-6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidine-2,4-diamine; Ν2-(4-(4-气-1Η-imidazol-1-yl)-3 -Methoxyphenyl)-indole 4-ethyl-indole 4-mercapto-7-phenyl-6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidine-2,4-diamine; (S) -Nf2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)-indole 4-ethyl-indole 4-indolyl-7-phenyl-6,7-di Hydrogen-5Η-cyclopenta[d]pyrimidine-2,4-diamine; (R)-N2-(4-(4-Ga-1Η-imidazol-1-yl)-3-methoxyphenyl) -Ν 4-B 149653.doc -6- 201107311 '-Methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; Azetidine- 1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxy-1-ylphenylphenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidine-2-amine; (S)-4-(azetidin-1-yl)-N-(4-(4-a-1H-imidazol-1-yl)-3-methoxyphenyl )_7· Stupid _6,7_Dihydro-5H_cyclopenta[d]pyrimidine-2-amine; (R) _4-(azetidin-imidazole-indole-yl)_3_nonyloxybenzene -7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; imidazolium-yl)"methoxyphenyl)_;^4_indolyl- 7·Phenyl·6,7·dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; (S)-N2-(4-(4-chloro-1H-imidazole-bu) -3-decyloxyphenyl)-N4-mercapto-7-phenyl-6,7-dihydro-5H-cyclopenta[d]carcinoma-2,4-diamine; (R)-N2 -(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-indolyl-7-phenyl-6,7-dihydro-5H-cyclopenta[ d]pyrimidine-2,4-diamine; Ν2·(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-cyclopropyl-7-phenyl- 6,7-dihydro·5Η_cyclopenta[d]pyrimidine-2,4-diamine; N2-(4-(4-gas·1Η-imidazole- 1-yl)-3-decyloxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-511-cyclopenta[£1]pyrimidine-2,4-diamine; ^-('('Chloro-old-imidazol-1-yl)-3-decyloxyphenyl)-indole 4-isopropyl-7-phenyl-6,7-dihydro-5Η-cyclopenta[ d]pyrimidine-2,4-diamine; Ν2-(4-(4-气_1Η-imidazole-buyl)_3·decyloxyphenyl)_7_(4-fluorophenyl)-fluorene 4-fluorenyl _ 6,7-dihydro-5Η_cyclopenta[d]pyrimidine_2,4-diamine; (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methyl Oxyphenyl)-7-(4-fluorophenyl)_N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; 149653.doc 201107311 (R )-N -(4-(4-gas_old_imidazolyl))_3_methoxyphenyl)_7·(4_fluorophenyl)-Ν4_methyl-6'7-dioxin·5Η_ Cyclopenta[d] stagnation _2,4_diamine; N2_(3_fluoro_4_(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)_7-(4_fluoro Benzo)-N4-mercapto-6,7-dihydro-5H_cyclopenta[d]pyridinium-2,4 diamine; N-(2-dun-5-methoxy_4_(3_f group) · Triazole·indolyl)phenyl)-7-(4-fluorophenyl)indole 4-methyl-6,7-dihydro-5H-cyclopenta(4)pyrimidine-2,4-diamine; N- (6-(4-Ga-1H-imidazole_1β-based)_5_methoxypyridine_3_yl _7_(4_ fluorophenyl)-Ν4-methyl_6,7-diaza-5Η_cycloindole[d] bleed-2,4-diamine; N-(4-(4-gas-1H- Imidazolyl)_3_decyloxyphenyl)4 (3,3-difluoroazacyclobutan-1-yl)_7_(4_phenylene)-6,7-diaza_5Hcycloindole (4) pyrimidine- 2-amine; 4_(3,3-difluoroazetidin-1-yl)-N-(3-fluoro-4-(5-mercapto-1H- 1,2,4·diazole_1 _ base) stupid)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; 4 - (3,3 - two gas Nitrogen ^ machine milk % butane _ _ _ _ _ _ (3_ fluoro_4 (5 methyl _lH_ - sit 1 base) stupid)-7-(4-fluorophenyl)-6,7-two Hydrogen-5H-cyclopenta[d]pyrimidinamine; (3'3-fluoro-cyclobutane-1-yl)-indole-(3-1-4-(5-methyl-1H- 1, 2'4'2° sitting _1_base) Stupid)·7·(4-phenylene)-6,7-dihydro-5Η-cyclopenta[d]pyrimidinamine; _ Ν (4·( 3_Chloro-out·1,2/-trimethyl-1-yl)-3-methoxyphenyl)-4-(3,3-aza-nitroso-indolyl-1'yl)-7-(4 -fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; 149653.doc 201107311 a (4-(3-chloro-1H-12〆-triazole-1- Base)_3_methoxyphenyl)·4_(3,3-fluoroazetidine-1· Fluorophenyl)·6,7-dihydro-5Η·cyclo-di-pyrimidinium i-amine; ^open^(4'(3,chloro-1Η-1,2,4-triazol-1-yl)_3_ Methoxyphenyl)_4(33_monoindole-butane-1·yl)-indole 4-fluorophenyl)-6,7-dihydro-5Η-cyclopenta[d]pyrimidinamine; corpse ^08 ,48)-2.Oxy-5-azabicyclo[2_2.1]hept-5-yl)-N-(4-(4-gas-1H-imidazolyl)_3_methoxyphenyl)_7_( 4-fluorophenyl)6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-amine; _4~((lS'4S)-2-oxo-5-azabicyclo[2.2.1M _5_ Base)_n_(4_(4_chloro_1Ή_imidol)-3·methoxyphenyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d Pyrimidine·2_amine; 4~((1S'4S)-2U_azabicyclo[2 2"]hept-5_yl)_n_(4_(4_chloro_1H_^saltyl)-3_decyloxy Phenyl)-7-(4-phenylphenyl)-6,7-di-argon-5H-cyclopenta[d]pyrimidine-2-amine; N-(4_(4_chloro'1H-imidazole·1- ))-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(2-indolyl oxime-small base >6,7-diaza-5η_cycloindole (4) · 2-amine; Ν_(4·(4_氯·1Η_咪. -1--1-yl)-3-decyloxyphenyl)-7-(4-buccinyl)-4-(2-methyln-pyridyl-1-yl)&gt;6,7-dihydro- 5η•cyclopenta(4)pyrimidine 2-amine; Ν-(4_(4_乳ΗΗ-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)4_(2 _Methyl. slightly bite. 1-yl)-6,7-dihydro-5H-cyclopenta-2-amine; 149653.doc 201107311 ν·(4-(4-chloro-1H-imidazole+yl)_3 _Methoxyphenyl)_7 (4-fluorophenyl)-4-(2-indolyl guanidinyl) _6 7•Dihydro-5H-cyclopenta(4)pyrimidine-2-amine; ν_(4 -(4·Gas-1H-Misin_丨_yl)_3_Methoxyphenyl)_7_(4_Phenylphenyl)-4-(2-indolyl hydrazinyl) _6,7 Hydrogen_5Η_cyclopenta(4)pyrimidine-2-amine; N-(4-(4-chloro-1H-miso-indenyl)3-methoxyphenyl-fluorophenyl)-4-(2) - 曱基. Specific to each mouth. 定小基) 6,7_二氮_5h_cyclopenta (4) biting _ 2-amine; n_(4-(4-chloro-1H-mazole small group)_3曱Oxyphenyl)4((2S6R)_ 2,6·dimethyl(N-morphinyl)(m〇rph〇lin〇)-7-(4-phenylene)-6,7-di Hydrogen-5H-cyclopenta[d] ringing _2_amine; N-(4-(4-chloro-1H-imidazolyl)yl)_3_decyloxyphenyl)_4 ((2S,6R)_ 2,6-methyl Morpholinyl))-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]»密〇定_2-amine; N-(4-(4_气- 1H-imidazolyl)_3_methoxyphenyl)_4_((2S,6R)_ 2,6-diindenyl (indolyl), 7-(4-phenylene) 6,7-dihydrol · 5H cyclopenta[d]pyrimidinamine; 1-(2_(4-(4- gas·1Η•imidazol-1-yl)-3-decyloxyphenylamino)-7-(4-fluorobenzene ,6,7-dihydro-5Η-cyclopenta[d]pyrimidin-4-yl)-4-mercaptopiperidin-4-ol; N_(4-(4-Ga-1H-imidazolyl)-3 _Methoxyphenyl)·4_(2_ethyl tonolidine _1 yl fluorophenyl)-6,7-dihydro-5 fluorene-cyclopenta[d]pyrimidin-2-amine; 149653.doc 201107311 N-(4-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(2-ethylindoleridin-1-yl)-7-(.4 -fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-oxime Phenyl)-4-(2-ethyloxaridin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- Amine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-ethyl. Bilpyridin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-gas- 1H-imidazolium-1-yl)-3-indolylphenyl)-4-(2-ethyl.pyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(2-B -Byrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; , 4-(4-Amino 4-mercaptopiperidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N2-(3-fluoro-4-(5-mercapto-1H-1,2,4-triazole-1- Phenyl)-7-(4-fluorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; N2-(3- Fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-]^4-methyl-6,7- Dihydro-5; «-cyclopenta[(1]pyrimidine-2,4-diamine; N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazole-1) -yl)phenyl)-7-(4-fluorophenyl)-&gt;14-methyl-6,7-dihydro-5:«-cyclopenta[(1]pyrimidine-2,4-diamine ; 149653.doc • 11 · 201107311 1-(2-(4-(4-气-1H-咪) Zin-1-yl)-3-methoxyphenylamino)_7_(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(three Fluoropyridyl) pyrrolidin-3-ol; 1-(2-(4-(4-gas-111-.m's-1-1-yl)-3-methoxyphenylamino)_7_(4_ Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-(trifluoromethyl)pyrrolidin-3-ol; 1-(2-(4) -(4-chloro-1Η-_ ° sit-1-yl)-3-methoxyphenylamino)_7_(4·fluorophenyl)-6,7-dihydro-5H-cyclopenta[d密密定_4_基)_3_(Trifluoromethyl)pyrrolidin-3-ol; 1-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-anthracene Phenylamino)7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]. _4_yl)_3-(trifluoromethyl) ° ratio 0 bites -3 -Alcohol; N-(4-(4-Gas-1H-imidazol-1-yl)-3-methoxyphenyl)_4_(3-(didecylamino). - 7-(4-fluorophenyl)_6,7·dihydro-5H cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)- 3-methoxyphenyl)_4_(3-(dimethylamino). Bilobidine-1-yl)-7-(4-fluorophenyl)_6,7-dihydro-5H_cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H) -imidazol-1-yl)-3-methoxyphenyl)_4_(3-(dimethylamino)° ratio leptin-1-yl)-7-(4-fluorophenyl)-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl) -4-(4-mercaptopiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; 149653.doc -12· 201107311 N-(4- (4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6, 7-Dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-( 4-fluorophenyl)-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4 -chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(piperazin-1-yl)-6,7-dihydro-5H -cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl) 4-(3-(decylamino)pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-amine, Ν-(4-(4 -chloro-1Η-imi Zin-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-(3-(methylamino)azetidin-1-yl)-6,7 -dihydro-5 fluorene-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(3 -(diammonium)azetidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; Ν2 -(3·fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-:^4-methyl- 6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxybenzene -7-(4-fluorophenyl)-4-((S)-3-fluoropyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine- 2-amine, Ν-(4·(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)_4-((S)-3- Fluoropyridin-1-yl)_6,7-dihydro-5Η-cyclopenta[d]pyrimidine 149653.doc -13- 201107311 pyridine-2-amine; N-(4-(4-gas-1H- Imidazolyl-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-4-((R)-3 -chloro 1 Dtb π π -1-decyl)-6, 7-diaza- 5H - 哀 戊 并 [d] 〇密11定-2 -amine, N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl) -7-(4-fluorobenzene ))-4-((R)-3 - gas D is more than sulphonyl-1-yl)-6,7-diaza- 5H - ί 戍弁 [d] 〇 ° ° -2 -amine), ^^(4-(4-Gas-111-imidazol-1-yl)-3-decyloxyphenyl)-4-(4,4-difluoropiperidin-1-yl)-7-(4- Fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxy Phenyl)-4-(4-fluoro-5,6-dihydroacridine-1(2H)-yl)-7-(4-fluorophenyl)-6,7-diargon-5H-cyclopenta [d]pyrimidin-2-amine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4-( 3-(trifluoromethyl). Bilobidine-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3 -nonyloxyphenyl)-N4-(3-ethoxypropyl)-7-(4-phenylphenyl)-6,7-di-rho-511-leaf 戍弁[(^]11密11定-2,4-diamine; 3-(2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenylamino)-7-(4-fluorophenyl) -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol; 7-(4-fluorophenyl)-N2-(3-methoxy-4 -(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2, 4-diamine; 149653.doc -14- 201107311 N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-(l-cyclopropyl-2 -methoxyethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; N2-(4-(4- Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-N4,N4-dimercapto-6,7-dihydro-5H-cyclopenta [d]pyrimidine-2,4-diamine; (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluoro Phenyl)-1^4,1^4-dimethyl-6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-diamine; (R)-N2-(4- (4-chloro-1H-imidazol-1-yl -3-decyloxyphenyl)-7-(4-fluorophenyl)-N4,N4-dimercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-di Amine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-trimethyl-6-7 -dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-7 -(4-fluorophenyl)-N4-((R)-1-decyloxybutan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-di Amine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4 -fluorophenyl)-6,7-dihydro-5H-cyclopenta[pyridyl-2.4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-oxime Phenyl)-N4-((S)-1-cyclopropylethyl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[(1]pyrimidine-2.4 - diamine; N2-(4-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-indolyl-8- 149653.doc -15- 201107311 Phenyl-7 , 8-dihydro-5H-pyrano[4,3-d], biting, 2,4-diamine; Ν2-(4-(4-气-1Η-imidazol-1-yl)-3-methyl Oxyphenyl)_Ν4_fluorenyl_8_phenyl-7,8-dihydro-5--0 oxime [4,3-4]1| dense 11 _2 4-diamine · Ν2·( 4-(4- Gas-1Η-imidazol-1-yl)-3-methoxyphenyl)_ν4methyl_8_ Benzo-7,8-two-rat-511-|1 bottom 弁[4,3-(1] 11 _2 4 -diamine. Ν2-(4-(4-Ga-1Η-imidazol-1-yl)-3-methoxyphenyl)_Ν4ethyl_ Ν4-methyl-8-phenyl- 7,8-Dihydro-5Η-piperazino[4,3_d]pyrimidine_2,4-diamine; (S)-N2-(4-(4-chloro-1H-imidazol-1-yl)_3_曱oxyphenyl)_n4_ethyl-N4-mercapto-8-phenyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; (R -N2-(4-(4-Chloro-1H-amidosyl)_3_methoxyphenyl)_n4_ethyl-N4-indolyl-8-phenyl-7,8-dihydro-5H -pipelano[4,3-d]pyrimidine-2,4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)_3_methoxyphenyl)·Ν4,Ν4 _Dimethyl-8-phenyl-7,8-dihydro-511-pyrano[4,3-(1]pyrimidine-2,4.-diamine; (S)-N2-(4-( 4-ox-1Η-imidazole-indole_yl)_3_methoxyphenyl)_ν4,ν4_dimethyl-8-phenyl-7,8-dihydro-5Η-pyrano[4,3-d] Pyrimidine 2,4-diamine; (R)-N2-(4-(4-chloro-1H-. Mizozol-i_yl)_3_methoxyphenyl)_n4,n4_dimercapto-8-phenyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine_2,4 _Diamine; 8-(4-fluorophenyl)-N2-(3-methoxy-4-4-(3·indolyl-1Η-1,2,4-=oxazol-1-yl)phenyl)-N4 ·Methyl-7,8-dihydro·5Η-piperazino[4,3-d]pyrimidine_2 4 149653.doc -16- 201107311 Diamine; N4-ethyl-8-(4-fluorophenyl -N2-(3-decyloxy-4-(3-methyl-1H-1.24-triazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4] , 3-d]pyrimidine-2.4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4- Fluorophenyl)-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl) )-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((R)-3-fluoroindol-1-yl)-7,8-dihydro-5H-piperidin N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorobenzene 4-((R)-3-fluoro.pyrrolidin-1-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine; N- (4-(4-Chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidine-1 -yl)-7,8-dihydro-5H-pyran And [4,3-d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-fluorophenyl --4-((S)-3-fluoropyridin-1-yl)-7,8-dihydro-5H-piperazino[4,3-d]pyrimidin-2-amine; N4-ethyl -N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-7,8-di Hydrogen-5H-pyrano[4,3-d]pyrimidine-2,4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl) 8-(4-fluorophenyl)-N4-mercapto-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; N2-(4-( 4-Q-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorobenzene 149653.doc -17- 201107311 base)-N4,N4-dimercapto-7,8 - dihydro-5H-piperazo[4,3-d]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxybenzene -N4-ethyl-8-(4-fluorophenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine ; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8 -(4-fluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine; I N2-(4-(4-Ga-1H-imidazole-1 -yl)-3-decyloxyphenyl)-8-(4-phenylphenyl)-N4 -mercapto-7,8-dihydro-5H-pyrano[4,3-(1]pyrimidine-2,4-diamine; N2-(4-(4- gas-1H-0 m D sitting- 1-yl)-3-decyloxyphenyl)-8-(4-propenyl)-N4-mercapto-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine- 2,4-diamine; N2-(4-(4- gas-1Η-σ米0坐-1-yl)-3-decyloxyphenyl)-8-(4-carbyl)-Ν4- Methyl-7,8-dihydro-5-pyrido[4,3-d]pyrimidine-2,4-diamine; Ν2-(4-(4- gas-1Η-σ米哇-1-yl) -3-oxooxybenyl)-8-(4-nitrogenyl)-1^4,:^4-dimercapto-7,8-dihydro-511-pyrano[4,3-( 1]pyrimidine-2,4-diφ amine; Ν2-(4-(4-chloro-1Η-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-chlorophenyl)- Ν4,Ν4-dimethyl-7,8-dihydro-5Η-piperazino[4,3-d]pyrimidine-2,4-diamine; Ν2-(4-(4-chloro-1Η-imidazole- 1-yl)-3-methoxyphenyl)-8-(4-phenylphenyl)-:^4,&gt;14-dimercapto-7,8-dihydro-511-pyrano[4] , 3-(1]pyrimidine-2,4-diamine; Ν-(4-(4-Ga-1Η-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-chlorobenzene 149653.doc -18- 201107311 yl)-4-(3,3-difluoroazetidin-1-yl)-7,8-dihydro-511-piperido[4,3-d]pyrimidine -2-amine; N-(4-(4-gas-1H) -imidazol-1-yl)-3-decyloxyphenyl)-8-(4-chlorophenyl)-4-(3,3-difluoroazetidin-1-yl)-7,8 - dihydro-511-piperacino[4,3-d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)- 8-(4-Phenylphenyl)-4-(3,3-dioxaza-d-denyl-1-yl)-7,8-diaza-5Η-Π底弁 [4,3-d] Pyrimidin-2-amine; 8-(4-chlorophenyl)-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)- N4,N4-dimercapto-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; 8-(4-chlorophenyl)-N2-(3 -fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-N4,N4-dimercapto-7,8-dihydro-5H-pyrano [4,3-d]pyrimidine-2,4-diamine; 8-(4-chlorophenyl)-N2-(3-fluoro-4-(5-methyl-111-1,2,4-tri) Zin-1-yl)phenyl)-N4,N4-dimethyl-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; 8-(4 -Phenylphenyl)-4-(3,3-dioxazapine-butan-1-yl)-^'[-(3-gas-4-(5-mercapto-1H-1,2,4 -triazol-1-yl)phenyl)-7,8-dihydro-5H-piperazino[4,3-d]pyrimidin-2-amine; 8-(4-chlorophenyl)-N2-( 3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H- 4-(4-chlorophenyl)-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4) -triazol-1-yl) 149653.doc -19· 201107311 Phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-di Amine; 8-(4-phenylphenyl)-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-indenyl -7,8-diar-5H-piperazop[4,3-d]pyrimidine-2,4-diamine; 8-(4-phenylphenyl)-N2-(3-decyloxy-4- (4-methyl-1H-imidazol-1-yl)phenyl)-N4-mercapto-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine ; 8-(4-chlorophenyl)-N2-(3-decyloxy-4-(4-indolyl-1H-imidazol-1-yl)phenyl)-N4-methyl-7,8-di Hydrogen-5H-piperazolo[4,3-d]pyrimidine-2,4-diamine; 8-(4-phenylphenyl)-N2-(3-decyloxy-4-(4-indolyl)- 1H-imidazol-1-yl)phenyl)-N4-mercapto-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-diamine; 8-(4- Phenyl)-N2-(3-decyloxy-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-indolyl-7,8- Dihydro-5H-piperacino[4,3-d]pyrimidine-2,4-diamine; 8-(4-phenylphenyl)-N2-(3-decyloxy-4-(3-methyl) -1H-1,2,4-triazole-l-yl)phenyl)-N4-methyl-7,8- Hydrogen-5H-pyrano[4,3-d]pyrimidine-2,4-diamine; 8-(4-phenylphenyl)-N2-(3-decyloxy-4-(3-methyl-) 1H-1,2,4-triazol-l-yl)phenyl)-N4_mercapto-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine-2,4-di Amine; 8-(4-bromophenyl)-N2-(4-(4-gas-1H-imidazol-1-yl)-3-methoxybenzene 149653.doc •20·201107311 base)-N4-A -7,8-dihydro-5H-piperazo[4,3-d]pyrimidine-2,4-diamine; 8-(4-bromophenyl)-N2-(3-fluoro-4-() 5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine_ 2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-4-((S )-2-mercaptopyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine. -2 -Amine, φ N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-indole-fluorophenyl)-5, 7-Dihydrofuro[3,4-d]pyrimidine-2,4-diamine; 1^2-(4-(4-chloro-11^imidazol-1-yl)-3-decyloxyphenyl )-:^4-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine; N2-(4-(4) -chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d Pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-4- ((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine-φ 2-amine; N-(4-(4-chloro-1H- Imidazolyl-1-yl)-3-decyloxyphenyl)-7-(4-fluorophenyl)-4-((S)-3-fluoropyrrolidin-1-yl)-5,7-dihydro Furando[3,4-d]pyrimidin-2-amine; N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl) Phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-fluoro- 4-(5-Methyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4- d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(5-A) -1H-1,2,4-triazol-1-yl)benzene 149653.doc -21 · 201107311 yl)-7-(4-fluorophenyl)-5,7-dihydrofuran [3,4- d]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4 -mercapto-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-indole Oxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine; &gt; 1-( 4-(4-Gas-111-imidazol-1-yl)-3-decyloxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4- Fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-amine, Ν2-(4-(4-气-1Η-imidazol-1-yl)-3-methyl Oxyphenyl)-N4-((R)-1-cyclopropylethyl)-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2 , 4-diamine; N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-7-(4-fluorophenyl)- N4-mercapto-5,7-dihydrofuro[3,4-d]pyrimidine-2,4.-diamine; N-(4-(4-Ga-1H-imidazol-1-yl)-3 -Methoxyphenyl)-7-(4-fluorophenyl)-4-((R)-3-fluoro. Bilidine-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine. 2-Amine, N-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-((2S,6R)-2,6-dimethyl (N-morpholinyl))-7-(4-fluorophenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-2-amine; N2-(4-(4-chloro-) 1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-8-phenyl-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2 , 4-diamine; N2-(3-fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-8-phenyl- 6,8-diaza-5 Η - ** 弁 弁 [3,4-d]^. -2,4 -monoamine, N2-(3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl 149653.doc - 22-201107311 -8-phenyl-6,8-dihydro-511-piperacino[3,4-(1]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H) -imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6,8-dihydro-5H-pyrano[3,4-d Pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorobenzene -N4-mercapto-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazole- 1-yl)-3-decyloxyphenyl)-8-(4-fluorophenylφ-yl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro- 5H-pyrano[3,4-d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-8-(4 -fluorophenyl)-4-((R)-3-fluoropyrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine; N -(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-fluorophenyl)-4-((S)-3-fluoro. Pyridin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine; φ N-(4-(4-chloro-1H-imidazol-1-yl) )-3-methoxyphenyl)-8-(4-fluorophenyl)-4-((S -3-fluoro.Byrrolidin-1-yl)-6,8-dihydro-5H-pyrano[3,4-d]pyrimidin-2-amine; N2-(4-(4-chloro-) 1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-phenylphenyl)-N4,N4-dimercapto-6,7-dihydro-5H-cyclopenta[d Pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(4-phenylphenyl)-4- (3,3-difluoroazetidin-1-yl)-6,7-dihydro-51^cyclopenta[£1]pyrimidin-2-amine; 149653.doc -23- 201107311 N2-( 4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-phenylphenyl)-N4-indolyl-6,7-dihydro-5H-cyclo Pentero[d]pyrimidine-2,4-diamine; (S)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4 - gas phenyl)-N4-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; (R) -N2-(4-(4-gas-1H) -Mid'oxazol-1-yl)-3-decyloxyphenyl)-7-(4-phenylphenyl)-N4-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidine -2,4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(3,4-difluorophenyl)-&gt ;14,:^4-dimercapto-6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-di# amine; (S)-N2-(4-(4-gas -1H-imidazol-1-yl)-3-methoxy Phenyl)-7-(3,4-difluorophenyl)-N4,N4-dimercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2.4-diamine; (R) -N2-(4-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)-7-(3,4-difluorophenyl)-N4,N4-dimethyl- 6,7-dihydro-5H-cyclopenta[d]pyrimidine-2.4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)- 7-(3,4-Difluoroφphenyl)-indole 4-methyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4-diamine; (S) -N2-( 4-(4-Ga-1Η-imidazol-1-yl)-3-decyloxyphenyl)-7-(3,4-difluorophenyl)-N4-indolyl-6,7-dihydro- 5H-cyclopenta[d]pyrimidine-2,4-diamine; (11)-:^2-(4-(4-Ga-1^1-imidazol-1-yl)-3-indolylbenzene -7-(3,4·difluorophenyl)-^^-mercapto-6,7-dihydro-511-cyclopenta[(1]pyrimidine-2,4-diamine; N2-( 4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-indolyl-7- 149653.doc -24- 201107311 (4_(difluoromethoxy)-based group )-6,7-Dihydro-5 Η-cyclopenta[d] ° dense. 4 diamine; (S)-N2-(4-(4-chloro-1Η-σmoxazol-1-yl)-3-methoxyphenyl)_n4_methyl-7-(4-(three Fluoromethoxy)phenyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidine·2.4-diamine; (R)-N2-(4-(4-Ga-1H-imiline-1 -yl)-3-decyloxyphenyl)-n4-methyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine 2.4 - diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-n4-ethyl-7-(4-(difluoromethoxy)benyl)- 6,7-two gas - 5H-cyclic 戍[ &lt;^] Mouth-dosing - 2 4 diamine; (S) -N2-(4-(4-chloro-1H-imidazol-1-yl)-3-indolyloxyphenyl)-7-ethyl- 7-(4-(Trifluorodecyloxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2.4-diamine; (R) -N2-(4-(4- Gas-1H-imidazol-1-yl)-3-methoxyphenyl, ethyl-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta [d]pyrimidine 2.4-diamine; N_(4-(4-Gas-1H-imidazol-1-yl)_3_methoxyphenyl)_4_(3,3_dioxazacyclobutane-1- -7-(4-(Trifluoromethoxy)phenyl)_6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; (S) -N-(4-(4- Chloro-1H-imidazol-1-yl)·3-methoxyphenyl)_4·(3,3_^fluorooxetane-bu)_7_(4·(trifluoromethoxy)phenyl) ·6,7_二风·5ί1'cyclopenta[d]pyrimidin-2-amine; (R) 'N'(4'(4-chloro_1H-imidazol-1-yl)-3-decyloxy Phenyl)_4_(3夂149653.doc -25- 201107311 difluoroazetidine_i_yl)·7·(4_(trifluoromethoxy)phenyl)_6,7_diindole-5Η- Cyclopenta[d] mouth. _2_amine; 2 N -(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl 7_(4-(trifluorodecyloxy)benzene (6)-N-(4-(4-chloro-1H-imidazolyl) oxime Phenyl)N4,N4_dimercapto-7-(4-(trifluorodecyloxy)phenyl)_6,7-dihydro-5H cyclopenta[d] succinctyl-2,4-diamine (R)_N • gas_1H_imidazol-1-yl)-3-methoxyphenyl)-N4,N4-methyl-7-(4-(trifluoromethoxy)phenyl)_6, 7_Dihydro-5H cyclopenta [leaf. Ding-2,4-diamine; 4 (azetidinyl)-N-(4-(4-gas-1H-imidazol-1-yl)-3_decyloxyphenyl"_(4_ (trifluoromethoxy)phenyl)·6,7-dihydro-5H-cyclopenta[d] chito-2-amine; (8) ice (azetidinyl)-N-(4- (4-Ga-1H-Min. Sodium)-3-Methoxyphenyl)·7·(4_(Trifluoromethoxy)phenyl)·6,7-Dihydro-5H-cyclopentyl And [d]pyrimidin-2-amine; ()(aza-5-butane-1·yl)-N-(4-(4-gas-1H-imidazol-1-yl)-3_f-oxy-based) '7'(4-(Trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; •26- 1 6,7_一虱-5 »-Cyclopenta[(1]pyrimidine-2,4-diamine; one (gas ~1H-imidazol-1-yl)-3-methoxyphenyl)·Ν4_methyl_7_ (3,4 ,5_Trifluorophenyl)-6,7·dihydro-5Η-cyclopenta[d].Metidine·2,4-diamine; 149653.doc 201107311 (S)-N2-(4-(4 -chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H- Cyclopenta[d]pyrimidine-2,4-diamine; (R)-N2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-indole -7-(3,4,5-trifluorophenyl)-6,7-dihydro-5^cyclopenta[ Pyrimidine-2,4-diamine; N2-(3-fluoro-4-(5-methyl-1H-1,2,4-tris-s-l-yl)phenyl)-N4-indolyl-7- (3,4,5-trifluorophenyl)-6,7-dioxin-5H-cyclopenta[d]pyrimidine-2,4-diamine; N2-(6-(4-gas-1H-imidazole) -1-yl)-5-decyloxypyridin-3-yl)-N4-mercapto-7-(3,4,5-trifluorophenyl)-6,7-diar-5H-cyclopenta [d]pyrimidine-2,4-diamine; N2-(4-(3-gas-1H-1,2,4-triazol-1-yl)-3-decyloxyphenyl)-N4-indole -7-(3,4,5-trifluorophenyl)-6,7-,dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; N-(4-(4- Chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-(3,3-difluoro.pyrrolidin-1-yl)-7-(3,4,5-trifluoro Phenyl)-6,7-dihydro-5^1-cyclopenta[(1]pyrimidin-2-amine; (S)-N-(4-(4- gas-111-° m. sitting-1 -yl)-3-decyloxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro -5H-cyclopenta[d]pyrimidin-2-amine; (R)-N-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-4-( 3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-511-cyclopenta[d]pyrimidin-2- Amine; 149653.doc -27- 201107311 N-(4-(4-Ga-1H-imiwa-1-yl)- 3·decyloxyphenyl)_4_(3,3·difluoroazetidin-1-yl)-7-(3,4,5-trifluorophenyl)·6,7-dihydro_5Η _cyclopenta[d]pyrimidine-2-amine; N2'(4-(4-chloro-1H-imidazo-buyl)-3-decyloxyphenyl)_7_(2,4-difluorophenyl) -Ν4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; (S)'n2_(4-(4-Ga-1H-imidazol-1-yl) -3·methoxyphenyl)-7_(2,4-difluorophenyl)-N4-indolyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine_2,4-diamine (R)-N2-(4-(4-Gas-1H-isoazol-1-yl)-3-decyloxyphenyl)-7-(2,4-difluorophenyl)-N4-methyl -6,7-dihydro-5Η·cyclopenta[d]pyrimidine-2,4-diamine; Ν2·(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxybenzene _N4-ethyl-7-methylphenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; N2-(4-(4-gas-1H-) Miso-1-yl)-3-decyloxyphenyl)_N4_ethyl_7_ dibasic-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2, 4-diamine; Ν2, (4·(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenyl)_8_(3,5-difluoro·indolyl)-indole 4-ethyl-7 , 8 - dihydro-5 Η-α bottom. South and [4,3-d] mouth. -2,4-diamine; N2'(4-(4-gas·1Η-imidazol-1-yl)-3-decyloxyphenyl)_8_(3,4-difluorophenyl)-indole 4- Ethyl-7,8-dihydro-5-pyrido[4,3-d]pyrimidine-2,4-diamine; N-(4-(4-chloro-1H-imidazol-1-yl)- 3-decyloxyphenyl)_4_(3,3-difluoroazetidin-1-yl)-8-(3,4-difluorophenyl)·7,8-dihydro-5H-piperidyl喃[4,3-d] cancer D-di-2-amine; 149653.doc -28 · 201107311 Ν2·(4-(4-Ga-1H_imidazole d•yl)_3_methoxyphenyl)_8 (3,4-difluorophenyl)_N4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diamine; 8_(3,4-difluorophenyl) )-N4-ethyl-N2-(3_fluoro-4-(5-fluorenyl-1H-1,2,4-oxadiazol-1-yl)phenyl)-7,8-dihydro-5H-pyran [4,3 d]pyrimidine_2,4·diamine; N2-(4-(4-Chloro-1H-imidazolium-yl)-3-methoxyphenyl)-N4_((8) sm-cyclopropylethyl)-8-(4-(trifluoromethyl)phenyl)-7 , 8-dihydro-5H-pyrano[4,3-&lt;1]pyrimidine-2,4-diamine; N2-(4-(4-gas_1H-imidazole-yl). Phenyl)_N4-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-piperazino[4,3-d]pyrimidine·2.4-diamine; N4-ethyl -N2-(3-|l-4-(5-methyl)indole, 'triazolyl)phenyl)-8-(4-(disindolyl)phenyl)-7,8-dihydro_ 5 piroxicam and [4,3 dw pyridine-2,4-diamine; N2-(4-(4-nitro-1H-imidazolyl)-3-methoxyphenyl)_N4_methyl _ 8 -(4-(difluoroindolyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2.4-diamine; d_yl)_3_methoxyphenylamino )_4_(ethylamino)-7'8-dihydro-5H-pie. Nanhe [4,3_d] 〇 _8 base) benzonitrile; N2-(4-(4-Ga-1H-imidazolyl)_3_methoxyphenyl)·Ν4·methyl· 8-( 4-(tri-1methoxy)phenyl)_7,8·digas_5Η•Pheno[4,3_d]pyrimidine _ 2.4-diamine; N-(4-(4-chloro-1H-imi) Squatting -1_yl)-3-methoxyphenyl)-4-((R)-3-fluoro 149653.doc -29- 201107311 匕 定 -1-yl)-8-(4-(three Fluoromethoxy)phenyl)-7,8-dihydro-5H-pyrano[4'3'd]pyrimidin-2-amine; 2 / -(4-(4-Ga-1H-imidazole_1_) Base)_3·methoxyphenyl)_N4_ethyl_N-methyl-8-phenyl_5,6,7,8-tetrahydroquinazoline-2,4-diamine; (S)4 -N2-(4_(4_chloro_1H_-oxazolidine)3methoxyphenylethyl-N-methyl_8_phenyl_5,6,7,8-tetrahydroquinazoline_2 , 4_diamine; W-N2-(4-(4-chloro-m-flavor. Sodium+yl)_3_decyloxyphenyl)n4_ethyl-N4-methyl_8_phenyl_5 ,6,7,8_tetrahydroquinazoline _2, heart diamine; Ν·(4-(4-chloro-1H-imidazolyl)_3_methoxyphenylphenyl _ 5,6,7 , 8-tetrahydropyrene, _2_amine; N-(4-(4-chloro-1Η-imidazolyl)_3_decyloxyphenyl)μ·ethyl.8_(4-fluorophenyl)- Ν4-mercapto-5,6,7,8-tetrahydroquinazoline-2,4-diamine; Ν2-(4- (4-gas-ΙΗ-η-mazole small group)_3_decyloxyphenyl)8 (4-phenylphenyl)-N,N4-dimercapto-5,6,7,8-tetrahydroquinazoline _2,4-diamine; (S)-N2-(4-(4-Gas-1H-imidazolyl)_3_methoxyphenyl)_8_(heart fluorophenyl)-N,N4-di Mercapto-5,6,7,8-tetrahydroquinazoline_2,4-diamine; (R)-N2-(4-(4·gas-1H-miso)•yl)_3_methoxy Phenyl))_8_(4-fluorobenyl) N,N-mercapto-5,6,7,8-tetrahydroindole. Oscarine 2,4-diamine; N_(4-(4-chloro- ΙΗ-咪.Sit_丨_yl)3methoxyphenyl)-8 (4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline-2-amine; N2-(4- (4-Chloro-1H-imidazolyl)-yl)_3_decyloxyphenyl)-N4-indolyl-6-(indolyl)-8-phenyl-5,6,7,8-tetrahydropyridine And [4,3-d]pyrimidine j 4 diamine; S ~ N2-(4-(4-gas-1H-imidazole-bukib oxime oxyphenyl)6, long propyl 149653.doc •30 · 201107311 sulfonyl)-N4-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d] bleed _ 2.4-diamine; 2-(4-( 4-H-1H-imidazol-1-yl)-3-decyloxyphenylamino). 4-(ethylamino)-8-phenyl-7,8-dihydrogen ratio. And [4,3-d] is dense. Ding-6(5Η)-methyl formate; (2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenylamino)- 4 (ethylamino)-8- Phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(cyclopropyl)methanone; 1-(2-(4-(4-chloro-1Η-) Imidazol-1-yl)_3_decyloxyphenylamino)_4_(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3_(1]pyrimidin-6(511)- 2-(2-(4- ox-1 Η-. Indenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3_£1]pyrimidine_2,4-diamine; 1-(2-(4-(4- gas-1Η) -imidazol-1-yl)_3_methoxyphenylamino (ethylamino)-8-phenyl-7,8-dihydroindolepyrido[4,3_d]pyrimidine·6(5Η)-yl -2·(dimethylamino)ethanone; Ν2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenyl)_6_(cyclopropylsulfonyl)- N4-ethyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2.4-diamine; 1-(2-(4-(4-chloro-1Η) -imidazol-1-yl)_3_methoxyphenylamino>&gt; 4-(ethylamino)-8-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5Η)- Ethyl ketone; Ν2-(4-(4-chloro-1Η-imidani-1-yl) )__曱-oxyphenyl)_Ν4_ethyl_6_ 149653.doc •31 · 201107311 (ethylic)-8-phenyl-5,6,7,8-tetrazolium ratio σ and [ 4,3-d]n-densidine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazole-1 -yl)phenyl)-6-(methylsulfonyl)-8-phenyl-5,6,7,8-tetrahydroacridino[4,3-d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(5-mercapto-1H-1,2,4-triazol-1-yl)phenyl)-6-(methylsulfonyl)-8- Phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine; 6-(cyclopropylsulfonyl)-N2-(3-fluoro-4 -(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)in 4-methyl-8-phenyl-5,6,7,8-tetrahydroacridine[ 4,3-(1]pyrimidine-2,4-diamine; 6-(cyclopropylsulfonyl)-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4- Triazol-1-yl)phenyl) is 4-indolyl-8-phenyl-5,6,7,8-tetrahydro. Bis-[4,3-(1]pyrimidine-2,4-diamine; 哀 propyl (4-(ethylamino)-2-(3- gas-4-(3-indolyl-1H-) 1,2,4 -2. Sitting _ 1 -yl) phenylamino)-8-phenyl-7,8-diaza. Specific ratio α[4,3 - d ]咕0定-6(5H )-based fluorenone; propyl (4-(ethylamino)-2-(3-hetero-4-(5-mercapto-1H-1,2,4-di-O-s-l-yl) Phenylamino)-8-phenyl-7,8-diaza. Ratio σ 弁 [4,3-d]n σ 定 _ 6(5Η)-yl) fluorenone; Ν4-ethyl-Ν2 -(3-fluoro-4-(3-methyl-1Η-1,2,4-triazol-1-yl)phenyl)-8-phenyl-6-(2,2,2-trifluoroethyl -5,6,7,8-tetrahydro.pyrido[4,3-d]pyrimidine-2,4-diamine; Ν4-ethyl-Ν2-(3-fluoro-4-(5- Methyl-1Η-1,2,4-triazol-1-yl)benzene 149653.doc -32- 201107311 yl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5 ,6,7,8-tetrahydroacridino[4,3-d]pyrimidine-2,4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-indole Oxyphenyl)-N4,N4-dimercapto-6-(nonylsulfonyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 2,4-diamine, N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4,6-dimethyl-8-phenyl-5, 6,7,8-four mice 11 degrees &lt;;1定弁[4,3-&lt;1] mouth °-2,4-diamine, N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazole- 1-yl)phenyl)-N4,6-diamidino-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-(1]pyrimidine-2,4-diamine; N2-(3-Fluoro-4-(5-fluorenyl-1H-1,2,4-triazol-1-yl)phenyl)-N4,6-dimethyl-8-phenyl-5,6 , 7,8 - tetranitrogen 0 is sigma 弁 [4,3-d] 0 dense. -2,4-diamine, N2-(4-(4-gas-1H-imidazol-1-yl)- 3-methoxyoxyphenyl)-N4-ethyl-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-di Amine; N4-ethyl-N2-(3-fluoro-4-(3-indolyl-1H-1,2,4-triazol-1-yl)phenyl)-6-mercapto-8-phenyl -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(5-mercapto-1H) -1,2,4-triazole-diyl)phenyl)-6-mercapto-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2, 4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4-indolyl-6- (Methanesulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine, Ν2-(4-(4-chloro-1Η-imidazole) -1-yl)-3-methoxyphenyl)-indole 4-ethyl-8-(4-fluorophenyl)-6-(nonylsulfonyl)-5,6 ,7,8-tetrahydroacridino[4,3-d]pyrimidine 149653.doc -33- 201107311 pyridine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(3) -methyl-1H-1,2,4-triazol-1-yl)phenyl)-8-(4-fluorophenyl)-6-(methylsulfonyl)-5,6,7,8- Tetrahydrogen. Bis-[4,3-d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-fluoro-4-(5-fluorenyl-1H-1,2,4-triazole- 1-yl)phenyl)-6-(methionine)-8-(4-amino)-5,6,7,8-tetra-rat 0-sigma-definite [4,3_d]pyrimidine -2,4-diamine; Ν2-(4-(4-Ga-1Η-imidazol-1-yl)-3-decyloxyphenyl)-indole 4,6-diethyl-8-(4-fluoro Phenyl)-indolyl 4-mercapto-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine; (4-(4-gas-111-imidazole- 1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorophenyl)-6-mercapto-5 ,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl )-4-(3,3-difluoroazetidin-1-yl)-8-(4-^phenyl)-6-(methyl continuation)&quot;5,6,7,8 - Tetrahydropyrido[4,3-d]pyrimidin-2-amine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl- 8-(4-Fluorophenyl)-N4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine; &gt;^-(4- (4-Chloro-111-imidazol-1-yl)-3-decyloxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-8-(4-fluorobenzene Base)-5,6,7,8-tetrahydropyrido[4,3-d] Acridine-2-amine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-(4-fluorophenyl)-N4,6-dimethyl 5-,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-di 149653.doc -34- 201107311 Amine; N2-(4-(4-chloro-1H-imidazole) -1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-6-mercapto-5,6,7,8-tetrahydropyrido[4, 3-d]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4-ethyl-8-(4 -fluorophenyl)-N4,6-dimethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine; φ N2-(4-(4 - gas-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-N4-methyl-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidine-2,4-diamine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-8-( 4-fluorophenyl)-4-((S)-3-fluoro° ratio σ each 0-decyl-1-yl)-7-(4-decyloxyphenyl)- 5,6,7,8- Four nitrogen. More than 11 [3,4-〇1]11-density &lt;1-diamine; Ν2-(4-(4-chloro-1Η-imidazol-1-yl)-3-methoxyphenyl) -Ν4-ethyl-8-(4-fluorophenyl)-7-(nonylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- , 4-diamine; N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4,7-diethyl-8-(4-fluorophenyl )-5,6,7,8-tetrahydrogen. Bis-[3,4-d]pyrimidine-2,4-diamine; 2-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenylamino)-4 -(ethylamino)-8-(4-fluorophenyl)-5,6-dihydroacridino[3,4-d]pyrimidin-7(8H)-decanoic acid decyl ester; 1-(2- (4.-(4-Gas-1H-imidazol-1-yl)-3-decyloxyphenylamino)-4-(ethylamino)-8-(4-fluorophenyl)-5,6 -Dihydro.pyrido[3,4-d]pyrimidine-7(8H)-149653.doc -35- 201107311 keto); N2-(4-(4-chloro-1H-imidazol-1-yl) )-3-methoxyphenyl)-N4-ethyl-8-(4-phenylphenyl)-N4-mercapto-7-(fluorite yellow-branched)-5,6,7,8-four氮[3,4-d]pyrimidine-2,4-diamine; N-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)- 8-(4-Fluorophenyl)-4-((R)-3-fluoropyridin-1-yl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyridine [3,4-d]pyrimidin-2-amine; N-(4-(4-chloro-1H-imidazol-1-yl)-3-decyloxyphenyl)-8-(4-fluorophenyl) -4-((R)-3 - defeated 0 piroxime. dec-1-yl)-7-(methyl aryl)-5,6,7,8-tetrazo. It is denser than the bite [3,4-d]°. N-2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-ethyl-8-(4-fluorophenyl)-7 -mercapto-5,6,7,8-tetrahydropyrido[3,4-(1]pyrimidine-2,4-diamine; N2-(4-(4-chloro-1H-imidazol-1-yl) )-3-methoxyphenyl)-N4-trimethyl-7-phenyl-6,7-diaza-511-3⁄4 penta[¢1]3⁄4. sec-2,4--amine , (S)_N2_(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-trimethyl-7-phenyl-6,7-dihydro- 5H-cyclopenta[d]pyrimidine-2,4-diamine; (R)-N2-(4-(4-Ga-1H-imidazol-1-yl)-3-decyloxyphenyl)-N4 -trimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; 2-(4-(4-chloro-1H-imidazole-1 -yl)-3-decyloxyphenylamino)-4-(decylamino)-8-phenyl-7,8-dihydroquinazolin-8-ol; 2-(4-(4- Gas-1H-imidazol-1-yl)-3-decyloxyphenylamino)-4-(decylamino)-8-phenyl-5,6,7,8-tetrahydroquinazoline-8 - alcohol; 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(dihydrogen 149653.doc -36·201107311 Amino)-7 -phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol; (6S,7S)-2-(4-(4-Ga-1H-imidazol-1-yl)_3 _曱Oxygen Phenylamino)-4-(dimethylamino)-7-phenyl-6,7-dioxin-5H-cyclopenta[d]pyrimidin-6-ol; N-(4-(4-chloro -1H-imidazol-1-yl)_3_methoxyphenyl)_4_(3_azetidin-1-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta [d]pyrimidine-2-amine; N-(4-(4-Ga-1H-imidazol-1yl)_3_decyloxyphenyl)_4_(3-fluoroazetidin-1-yl) -7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-amine; N-(4-(4-Chloro-1H-.m. sit-small)_3_methoxyphenyl)_4_(3-methoxyazetidin-1-yl)-7-styl 6,7 dihydro-5H cyclopenta[d]pyrimidin-2-amine; N-(4-(4·gas-ΙΗ-味状小基)_3_methoxyphenyl)_7_phenyl-4_ ( 5,8-Dioxy-2-cyclohexane [3.4]octyl)_6 7 dihydro-5H cyclopenta[d]-pyridin-2-amine; phenyl) 3 oxophenylamino)·7 benzene Alkyldihydro-5Η-cyclopenta- _4_yl)azetidinone; 1-(2-(4-(4-气-1Η-imidazole, ^ K group)·3-曱Oxyphenylamino)-7-(4-propenyl)-6,7-dichloro-5Η-cycloindole ... 乂[d]pyrimidin-4-yl)-3-indenylazetidine Alkyl-3-carbonitrile; N-(4-(4-gas-1H-imidazole-K, violent)~3_methoxyphenyl)-4-(3-ethoxyazetidine- 1-yl)-7-(4-gombie* as a base)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine; N-(4-(4-gas-1H) -Imidazole·丨_其,, ,暴)-3·methoxyphenyl)-7-phenyl_4-(5-oxo-2-aziro[3.4]oct-2-yl-two' plant Hydrogen-;5H-cyclopenta[d]pyrimidin-2-amine; 149653.doc 37. 201107311 gas_1Η_σ米0 sit small base)·3-methoxyphenyl Base) ι (4 Π , dihydro Cyclopentylene _-4_ Η Η 甲基 甲基 甲基 - - 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 )_3_methoxyphenyl)4 (3 base-based heterozygous butyl group)-7-(4-fluorophenyl)·6,7-diaza-5Η_cyclopenta[d]pyrimidine_2 _amine; N-(4'(4-Ga-1H-imidazol-1-yl)_3_methoxyphenyl)_7 (4-fluorophenyl)-4-(3_decyloxy_3_A Azetidine-indenyl) 6,7-dihydro-5-cyclopenta[d] mouth bite_2_amine; 7-(4-fluorophenyl)-4-(3-decyloxy- 3-mercaptoazetidine-丨-yl) (3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)_6,7 _ dihydro 5H-cyclopenta[d]pyrimidin-2-amine; 7-(2,4·monofluorophenyl)-N2-(3-indolyl-4-(3-indolyl-1H-1) , 2, sit-1-yl)phenyl)-N4-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; (S)-7-(2, 4-difluorophenyl)-N2-(3-decyloxy-4-(3-indolyl-1H-1 〇4-dioxan-1-yl)phenyl)^4-indolyl-6, 7-Dihydro-511-cyclopenta[(1] oxime. _ 2.4-diamine; (R)-7-(2,4-difluorophenyl)-N2-(3-decyloxy-4-(3-indolyl-1H-1,2 4-triazole) -1-yl)phenyl)-N4.decyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine. _ 2.4-diamine; 6-(2,2-difluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(5-methyl-1H-1,2 4-triazole- 1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyridin-2,4-diamine; -38- 149653.doc 201107311 6 -(2,2-.monofluoroethyl)-N4-ethyl-N2-(3-fluoro-4-(3-methyl-1 1 4-triazol-1-yl)phenyl)-8 -phenyl-5,6,7,8-tetrahydropyrido[4,3_d]hexaidine_2,4-diamine; N4-ethyl-N2, (3-methoxy-4-(4- gas) -1H-13 -moxi-1_yl)#yl)-8-phenyl-6-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydropyrido[4 3 d]pyrimidine-2,4-diamine; N4-ethyl-N2-(3-methoxy-4-(4-chloro-1H-13-methane. sitting_ι·yl)~pyrimidine-2, 4-diamine; 8-(4-fluorophenyl)-N2-(3-decyloxy-4-(3-methyluh", 2,4,3.sodium 1-yl)phenyl)-N4 ,6-dimethyl- 5,6,7,8-tetrahydrogen. Ratio of n to 2.4-diamine; 8-(4-fluorophenyl)-N2-(3-methoxy-4-(5) -曱基_1 Η-1,2,4-di-1-yl)phenyl)-N4,6-dimercapto-5,6,7,8-tetrahydroindole ratio bite [4,3_( |]0^〇2.4-diamine; • (±)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)_4_ (methylamino) )- 7-phenyl-6,7-diin-5H-cycloindole[d] ηη定_5_鲷; (Ε)-2-(4-(4-chloro-1Η-_ &quot;sitting-1 -yl)-3-methoxyphenylamino)-4-(methylamino)-7-phenyl-6,7-dihydro-5Η-cyclopenta[d]^^_5-_〇- Methyl hydrazine; 2-(4-(4-Ga-1H-imidazol-1-yl)-3-methoxyphenylamino) kappamethylamino)-7-phenyl-6,7-dihydro - 5H-cyclopenta[(1]°3⁄4 bit-5-alcohol; N2-(4_(4-chloro-1H-imidazol-1-yl)-3·decyloxyphenyl)_N4_methyl-8 -phenyl-5,6,7,8-tetrahydroquinazoline-2,4-diamine; 149653.doc •39- 201107311 1-(2-methoxy-4-(4-(methylamino) )-7_phenyl_6,7_dihydro_5H_cyclopenta[d]0 dimethylamino)phenyl)-1H-imidazole- 4-indoleonitrile; Ν·(4-(4) - gas-1H-imidazol-1-yl)_3_methoxyphenyl)_7phenyl-indole (1,4-dioxo-7-azaspiro[4_4]fluoren-7-yl)-6,7- Dihydro-5Η-cyclopenta[d]pyrimidin-2-amine; 1-(2-(4-(4-Ga-1H-imidazol-1-yl)_3_nonyloxyphenylamino)7_ Stupid-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidine-3-enone; 4-(8-(cardofluorophenyl)_4_(decylamino)-6 -(曱sulfonyl)_5,6,7,8_tetrahydroanthracene is more than 0 [4,3-(1] guanidine-2-ylamino)benzene Nitrile; N2-(4-(4-(difluoroindolyl)·1Η-imidazole·bukib methoxyphenyl)_7_(4-fluorophenyl)-N4-indolyl-6,7-di Hydrogen_5Η·cyclopenta[d]pyrimidine_2,4-diamine; Ν2·(3_曱-oxy-4_(ι-methylpyrazole i-yl)phenyl)_like·曱基_ 7- Phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4 diamine; N-(2"gas_m_light+yl)_3_decyloxyphenylamino)_7 _Stupyl-6,7-dihydro-5Η·cyclopenta[d] σ 密一·基)·ν methyl 甲烧烧胺; Ν-(2 归气-(四)唾小基)·· Methoxyphenylamino)7·stupyl-Μ-dihydro·5Η,cycloindole-based)·ν_甲烧碌胺; Ν-(2-(4·(4-气mu)_3_ Foxyphenylamino)7-phenyl-6,7-dihydro-5Η•cyclopentacarbyl]-N-methylethylamine; +yl)_3•methoxyphenylamino Small 笨-Μ-dihydro-5 Η-cyclopenta[d] 喷 ^ 4 _ _ _ • 乙 乙 ; ; ; ; ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Phenyl)_ν4_(5isopropyl 149653.doc •40· 201107311 yl-2-methylphenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4 -diamine; 4-(4-(5-isopropyl-2-indolylamino)-7-phenyl-6,7-di -5}1-nitrile; 4·yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenyl N-mercapto-N2-( 2-mercaptopyridine, cyclopenta[d]pyrimidine-2,4-diamine; N2-(3-decyloxyphenyl)-N4-methyl[d][deg.]~2,4-diamine; phenyl-6,7-dihydro-5H-cyclopentyl N2-(4-fluorophenyl)_N4-indole [d]°^^-2,4-diamine; stupid-6,7-dihydro-5H-cyclopenta Methyl-N2-(3,5-difluorophenyl)-N4-[d]pyrimidine-2,4-diamine; N2-(4- gas-3-methoxyphenyl 5H-cyclopenta [d]Bite 2,4-diamine N2-(4_bromo-2-methoxyphenyl 5H-cyclopenta[d]» bite- 2,4-diamine 7~stupyl-6 ,7-Dihydro-5H-cyclopentyl)-indole 4-methyl-7-phenyl-67-dihydro-methyl-7-phenyl-6,7-dihydro-methyl-7-phenyl-6, 7-Dihydro-Ν2-(4-fluoro-3-hydroxyphenyl)phosphonium 4 5Η-cyclopenta[d]pyrimidine-2,4-diamine; N4-mercapto-7-7-phenyl; ^2_(pyrimidine [d]pyrimidine-2,4-diamine; 'yl)-6,7-dihydro-5H-cyclopenta-N4-mercapto-yl-N2 pyridinium·[d] Pyrimidine-2,4·diamine; earth)·6,7·dihydro-5Η-cyclopenta-4-(4-(decylamino)-7-phenyl·6,7,di-amp; Benzoquinone; 虱-5H~cyclopenta[d]pyrimidine_2- 149653.doc 201107311 4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopentyl And [d]pyrimidin-2-ylamino)benzonitrile; 4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2 -ylamino)benzonitrile; 2-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenylhydrazine Nitrile; 4-(4-(methylamino)-7-phenyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-2-ylamino)-1-naphthalenecarbonitrile; 5-(4-(decylamino)-7-phenyl-6,7-dihydro-5H- Cyclopenta[d]pyrimidin-2-ylamino)2-cyano d ratio 〇 定 in ( pic〇iinonitriie); 2-(4-(4-(nonylamino)-7-phenyl-6,7- Dihydro-5H-cyclopenta[&lt;1]pyrimidin-2-ylamino)phenyl)acetonitrile; 2-(4-(decylamino)-7-phenyl-6,7-dihydro-5H- Cyclopenta[d]pyrimidin-2-ylamino)-1Η-benzo[d]mi. Sodium-5-phthalonitrile; 3_(4_(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)benzonitrile; N2- (4-tert-butylphenyl)_N4_fluorenyl-7-phenyl-6,7-dihydro-511_cyclopenta[d] ytidine-2,4-diamine; N4·fluorenyl -N2_(4-(methylsulfonyl)phenyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d] mouth bite-2,4-diamine; N4-mercapto- 7-Phenyl-N2-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]. Bite 2,4-diamine; 4-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino) Benzodiazonitrile; 149653.doc -42· 201107311 4 (4-(Methylamino)-7-phenyl-6,7-dihydro-5H_cyclopenta(4)pyrimidin-2-ylamino)-2-( Trifluoromethyl)benzonitrile; N4-methyl-7-phenyl-N2_(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H_cyclopenta[d]. -2,4-diamine; 5-(4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)-2 , 3-dihydro-1H-inden-1-one; 2-(4-(methylamino)-7-phenyl.6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl Amino)-1Η-imidazole-4,5-dicarbonitrile; 2-bromo-5-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidine-2-ylamino)benzonitrile; N,N-dimethyl-4-(4-(decylamino)-7-phenyl-6,7-dihydro-5H_cyclopenta [d]pyrimidin-2-ylamino)benzamide; 1-(4-(4-(decylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d] Pyrimidin-2-ylamino)phenyl)cyclopentanecarbonitrile; N4-methyl-7-phenyl-N2-(l,2,3,4-tetrahydroisoquinolin-6-yl) -6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine; 4-(4-(methylamino)-7-phenyl-6,7-dihydro-5H- Cyclopenta[d]pyrimidin-2-ylamino)-2-(trifluoromethoxy)benzonitrile; 1-(4-(4-(decylamino)-7-phenyl-6,7 -dihydro-5H-cyclopenta(4)pyrimidin-2-ylamino)phenyl)cyclopropanecarbonitrile; 1-(2-methoxy-4-(4-(decylamino)-7-phenyl -6,7·dihydro-5H-cyclopenta[d]pyrimidin-2-ylamino)phenylamino)cyclopropanecarbonitrile; N4-methyl-N2-(2-mercapto-1H-indol-5-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-di Amine; 149653.doc -43· 201107311 N2-(benzofuran_5•yl)_N4methyl-7phenyl·6,7 dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine N2-(1H-»引ηη_5_yl)_曱yl_7_phenyl_6,7 dihydro_5h-cycloindole[(1]°3⁄4°定-2,4-diamine ; N4 methyl-N2_(2_methyl benzo[d]oxazole-6-yl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]carcinoma bite_2,4 Diamine; N2-(1H- benzo[d]imidazole-6-yl)·Ν4_mercapto_7_phenyl_6,7 dihydro-5H-cyclopenta[d] squirting _2, 4_diamine; N4-mercapto_Ν2·(1_mercapto]沁吲哚_5yl)_7_phenyl_6 7 dihydro-5Η-cyclopenta[d]pyrimidine_2,4-di Amine; N4-methyl-N2-(2-mercaptobenzo[d]thiazole-6(yl)-7-7-phenyl-6,7-diar-5H-cyclopenta[d] mouth bite_2, 4-diamine; N2-(4-bromomethoxyphenyl)_N4_methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine ; 1-(4-(4-(indenyl)-7-phenyl-6(dihydro-5H cyclopenta[d]pyrimidin-2-ylamino)phenyl)ethanone; N2-(4 -cyclopropylphenyl)_7_(4fluorophenyl)_n4_fluorenyl-6,7-dihydro-5H-cyclopenta [d]pyrimidine·2,4-diamine; Ν2-(4_B-phenylphenyl)-7-(4-d-phenylphenyl)-indole 4-methyl-6,7-dihydro-5Η-cyclopentyl And [d]pyrimidine_2,4-diamine; 7·(4·gasphenyl)hepta 4-methyl-Ν2·(4·(prop-1-ynyl)phenyl)-6,7-di Hydrogen-5Η-cyclopenta[d]pyrimidine-2,4 diamine; N2-(3-methoxy-4-(2-mercaptopyridin-4-yl)phenyl)-N4-methyl-7 -phenyl-6,7-dihydro-5Η-cyclopenta[d]pyrimidine-2,4 diamine; 149653.doc 201107311 N2-(3-methoxy-4-4-(acridin-4-yl) Phenyl)-N4-methyl-7-phenyl-6.7-dihydro-5H-cyclopenta[d]° sessile-2,4-diamine; and N2-(3-methoxy-4- (〇 咬-3-yl)phenyl)-N4-mercapto-7-phenyl·6.7-dihydro-5H-cyclopenta[d]pyrimidin-2,4-diamine; or its medicinal Acceptable salt. A pharmaceutical composition for treating a condition which is responsive to a decrease in the production of amylin-like peptides comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier A combination of agents or diluents. 16. A method of treating a condition responsive to a decrease in the production of amylin in a mammal in need thereof, comprising administering to the mammal a therapeutically effective stem of the compound of claim 1 or a pharmaceutically acceptable compound thereof salt. 17. The method of claim 16, wherein the condition is selected from the group consisting of AlZheimer's Disease 'AD, Down's syndrome (D〇wn Syndrome), mild cognitive impairment (MCI), and brain starch blood vessels. Disease (CAA), Lewy body dementia (dementia ~ 沘, ) amyotrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM), age-related macular degeneration and cancer. 18. The method of claim 17, wherein the condition is selected from the group consisting of Alzheimer's disease and Down's syndrome. 19. The method of claim 18, wherein the condition is Alzheimer's disease. 149653.doc -45- 201107311 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: (1) 149653.doc